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HEPATITIS C VIRUS

The hepatitis C virus was considered by a previous IARC Working Group in 1993 (IARC1994) Since that time new data have become available these have been incorporated inthe Monograph and taken into consideration in the present evaluation

1 Exposure Data

11 Taxonomy structure and biology

111 Taxonomy

In the 1970s and 1980s serological testsdeveloped or hepatitis A and B viruses (HAVHBV) indicated that most transusion-associ-ated hepatitis was not caused by either HAV orHBV and were thereore named non-A non-Bhepatitis (NANBH) Aer detection o the first

NANBH-specific clone the entire viral genomeo the now termed hepatitis C virus (HCV) wassequenced and based on its structural and unc-tional organization HCV was classified into theamily o the Flaviviridae where it orms its owngenus lsquohepacivirusrsquo (Choo et al 1989 Kuo et al 1989)

At least six major viral genotypes (1 to 6)have been identified (Simmonds et al 2005)Viral genotypes have specific geographic distri-

bution Te determination o the viral genotypeis important or transmission studies and hasmajor therapeutic implications Patients inectedwith genotype 1 have a significantly lower rate oresponse to antiviral therapy compared to othergenotypes (Manns et al 2007)

Genotypes display differences in nucleotide

sequences below 30ndash35 and within a genotypegenomes are allocated into different subtypesi their sequences differ by over 20ndash25Furthermore viral isolate(s) present in aninected individual can mutate into quasi-species(Simmonds et al 2005 Xu et al 2008)

112 Structure of the virion

In line with other members o theFlaviviridaeHCV consists o an enveloped nucleocapsid that

assembles intracellularly in close conjunctionwith membranes derived rom the endoplasmicreticulum (Moradpour et al 2007) ReleasedHCV particles are about 40ndash70 nm in diameterbut the morphology o particles detected in theserum o patients may be heterogeneous due tothe association with immunoglobulins or verylow density lipoproteins (vLDL) (Andreacute et al2005)

113 Structure of the viral genomeTe HCV genome is a single-stranded positive

sense RNA o approximately 96 kb and is repre-sented in Fig 11 It contains short non-codingregions (NCRs) at each end that encompass thecoding sequence o a polyprotein Te 5prime NCRa well conserved 341nt sequence element which

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IARC MONOGRAPHS 991251 100B

orms into a complex secondary structure isneeded or efficient RNA replication and drivescap-independent translation o a single largeopen reading rame (ORF) that encodes approxi-mately 3000 residues (Moradpour et al 2007)Te HCV 3prime NCR consists o a short variabledomain o about 40nt and a polyuridinepolypy-rimidine tract ollowed by a highly conserveddomain o 98nt that is essential or RNA replica-tion (anaka et al 1995) Te N -terminal regiono the polyprotein encodes the structural proteinsincluding the nucleocapsid protein (core) andtwo envelope glycoproteins (E1 and E2) thatorm the viral particle ollowed by several non-structural proteins designated as NS2 to NS5B

(Fig 11) Te C -terminal regions o the coreand envelope proteins contain signal sequencesand are cleaved in the endoplasmic reticulum byhost signal peptidase and signal peptide pepti-dase (Yasui et al 1998 McLauchlan et al 2002Okamoto et al 2004) Alternative cleavage sitesat the C -terminal o E2 yield the viroporin p7Te NS2NS3 junction is cleaved in cis by metal-loproteinase activity Te remaining cleavagesare carried out by the NS3 serine protease whichrequires NS4A as a coactor Besides partici-

pating in polyprotein processing NS2 playsimportant roles in viral assembly (Moradpour et al 2007 Jirasko et al 2008) Te non-struc-tural genes NS3 NS4A NS4B NS5A and NS5B have diverse unctions (see Section 4) and areall required or RNA replication (Lindenbach et al 2007 Moradpour et al 2007) NS5B the

viral replicase lacks prooreading activity Tislack o prooreading in the context o a veryhigh viral production rate which has been esti-

mated to be as much as 1012

virions per day ininected patients is thought to be responsible orthe high genetic variability o HCV (Moradpour et al 2007) Tus HCV has been classifiedinto six genotypes and several subtypes basedon sequence similarities In addition the HCVgenome is prone to acquiring mutations that

lead to the presence o quasi-species in inectedpatients (Xu et al 2008)

114 Host range

HCV is hepatotropic and only man andhigher primates such as chimpanzees have beenuntil recently receptive to HCV inection anddisease Later it was shown that the marmosetas well as tupaias which are members o thetree shrew genus are also susceptible to HCVinection (Shimizu et al 1998 Sung et al 2003Pachiadakis et al 2005)

115 Tissue target

While HCV RNA has been unequivocallydetected in the hepatocytes o liver biopsies ochronically inected patients and chimpan-zees the HCV genome has also been suggestedto replicate in cells o lymphoid origin anddendritic cells (Shimizu et al 1998 Sung et al 2003 Pachiadakis et al 2005) but this observa-tion remains to be substantiated Whether thetropism o HCV is limited to hepatocytes at thelevel o cell entry andor replication via the asso-

ciation o HCV with lipoproteins andor by otheractors remains unclear Expression patterns oall cell entry actors isolated to date are eitherubiquitous or not unique to hepatocytes Tisincludes the lipoprotein receptors scavengerreceptor B1 (SR-B1) and the low-density lipopro-tein receptor (LDLr) which may mediate indirectuptake o HCV via HCV-associated lipoproteins(Moradpour et al 2007) Te replication o HCVseems mostly restricted to hepatocytes and eventhough HCV replicons have been shown to

ampliy in cell lines o non-hepatic origin thelevels o replication reported are significantlylower than those observed in cell lines o hepaticorigin (Zhu et al 2003 Ali et al 2004 Chang et al 2006)

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Hepatitis C virus

116 Life cycle replication and regulation ofgene expression

Virus-binding to the cell surace and cellentry may involve the LDLr glycosaminoglycansSR-B1 the tetraspanin CD81 and the tight junc-tion actors Claudin-1 and Occludin (Evans et al 2007 Lindenbach et al 2007 Moradpour et al 2007 Plosset al 2009) Te tight junction actorsare thought to act at late stages o cell entry andtheir involvement in HCV cell entry suggests that

the state o polarization o hepatocytes is likelyto be important or the cell entry process (Evans et al 2007) Internalization occurs via clathrin-coated vesicles and their acidification inducesthe usion machinery o the HCV glycoproteinsLittle is known about the uncoating process andthe initial events that allow the assembly o repli-cation complexes IRES-mediated replication

polyprotein processing and virion assemblyRNA replication occurs in membrane-like websthat are ormed at the endoplasmic reticulumTe assembly and secretion process is thoughtto occur in tight relation with the vLDL biosyn-thesis machinery which may explain the possibleassociation o secreted HCV particles with vLDL(Andreacute et al 2005 Nielsen et al 2006 Miyanariet al 2007)

117 Diagnosis of HCV infection

Te diagnosis o HCV inection relies onlaboratory tests which include 1) anti-HCV anti-body detection assays relying on third-gener-ation enzyme-linked immunosorbent assays(ELISAs) whose sensitivity and specificity havebeen demonstrated 2) viral genome detectionassays mainly relying on real time Polymerase

137

Fig 11 The HCV genome structure viral polyprotein expression and processing into viral proteins

Reprinted by permission rom Macmillan Publishers Ltd Nature Review Microbiology Moradpour et al (2007) Copyright (2007) httpwwwnaturecomnrmicroindexhtml

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Chain Reaction (PCR) technologies allowing thequantification o the viral genome 3) genotypingassays to determine viral genotypes that allowthe prediction o treatment outcome and thedetermination o treatment duration (Zoulim 2006)

Te detection o anti-HCV antibodies inplasma or serum is based on the use o third-generation enzyme immunoassays (EIAs) thatdetect antibodies directed against various HCVepitopes Recombinant antigens are used tocapture circulating anti-HCV antibodies ontothe wells o microtitre plates microbeads orspecific holders adapted to closed automateddevices Te specificity o third-generation EIAs

or anti-HCV is greater than 99 and has beenimproved by the addition o viral epitopes thatare recognized by antibodies present in theserum o inected patients (Colin et al 2001)Teir sensitivity is more difficult to determinegiven the lack o a gold standard method but itis excellent in HCV-inected immunocompetentpatients EIAs can be ully automated and arewell adapted to large volume testing Immunoblottests are nowadays clinically obsolete given thegood perormance o third-generation anti-HCV

EIAs (Colin et al 2001)

12 Epidemiology of infection

121 Prevalence and geographic distribution

Te estimated prevalence o HCV inectionworldwide is 22 Region-specific estimatesrange rom lt 10 in northern Europe to gt 3in northern Arica (Fig 12 Alter 2007) Highprevalences o HCV (ge 10) were ound in someareas o Italy and Japan and most notably inEgypt (15ndash20) ollowing mass injection treat-ment or schistosomiasis More recently highHCV prevalences have been reported in someAsian areas notably in Pakistan (Ahmad 2004)and the Peoplersquos Republic o China (Zhang et al 2005) Within Europe the highest prevalence

rate o HCV inection was reported in southernItaly where 75 o the general population andup to 232 o those aged 65 years old or olderwho were randomly selected were HCV-inected(Fusco et al 2008) Te lowest prevalence (001ndash01) was reported or the United Kingdom andScandinavia

122 Transmission and risk factors forinfection

HCV can be transmitted by transusion oblood and blood products transplantation osolid organs rom inected donors injection drugabuse unsae therapeutic injections and occupa-tional exposure to blood (primarily contaminated

needles) (Alter 2007) ransusion-associatedHCV inection was an important source oinection beore HCV testing o blood donorswas introduced in the early 1990s Since thentransusion-associated HCV inection has been

virtually eliminated in those countries whereroutine HCV-testing has been implemented(Sae Injection Global Network (SIGN) 2001)Iatrogenic HCV transmission through unsae(therapeutic) injections has sustained substantialepidemics o the inection in Japan Italy in the1940s and Egypt in the 1950s and it is currently

very requent in low-resource countries (Ahmad 2004 Raza et al 2007) where disposable needlestend to be re-used and injections tend to bepreerred to the oral route or the administrationo common treatments It has been estimatedthat approximately 2 million HCV inections arecaused annually by contaminated health-care-related injections Injection drug use accountsor most o the newly acquired inections in

developed countries Te incidence rate amongnew drug injectors has been observed to rangerom 9 to 30 per 100 personndashyears (Des Jarlais et al 2003)

HCV is less efficiently transmitted by occupa-tional perinatal and high-risk sexual exposurescompared to those involving large or repeatedpercutaneous exposures to blood (Alter 2007)

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Hepatitis C virus

139

F i g

1 2

E s t i m a t e d p r e

v a l e n c e o f H C V i n f e c t i o n b y r e

g i o n

A d a p t e d f r o m A l t e r ( 2 0 0 7 ) d a t a s o u r c e W o r l d H e a l t h O r g a n i z a t i o n

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Te rate o transmission aer an accidentalneedle-stick injury involving HCV-positiveblood ranges rom 0ndash10 (Hernandez et al 1992 Mitsui et al 1992) Te rate o perinatalHCV transmission is 4ndash7 and occurs onlywhen HCV RNA is detectable in the maternalserum at delivery Tere has been no differencein the rate o HCV transmission between vaginaldelivery caesarian section or breasteedingHowever co-inection with HIV increases therate o transmission 4ndash5-old Te extent towhich HCV is transmitted by sexual activity is

very controversial (Alter 2007) Although casendashcontrol studies o acute hepatitis C have identi-fied sex with an inected partner or with multiple

partners as independent risk actors or acquiringthe disease in long-term monogamous relation-ships with a partner with chronic HCV inectionthere was little evidence or sexual transmissiono HCV (Clarke amp Kulasegaram 2006)

Currently the data are too scant to determinewhether cosmetic procedures (eg tattooingbody piercing) or intranasal illicit drug usesignificantly contribute to the overall HCVtransmission (Alter 2002 Hwang et al 2006)

123 Persistence latency and natural historyof infection

Persistence o HCV inection occurs in themajority o HCV-inected individuals HCVinection is oen asymptomatic Indeed acuteHCV inection whether symptomatic or notresolves spontaneously only in 10ndash40 o cases(Poynard et al 2003 Adhal 2004) PersistentHCV inection is characterized by the persistenceo elevated aminotranserase levels and HCVRNA in serum Serological distinction o chroniccarriers is difficult Chronically HCV-inectedpatients are in general asymptomatic and somereport nonspecific symptoms such as atigue orabdominal discomort Approximately 15ndash27o chronically inected patients are estimatedto develop cirrhosis Te time to progression to

severe liver disease is highly variable Factorsthat accelerate clinical progression include beingo masculin gender older at the age o inectionalcohol intake and co-inection with HIV andor HBV (Lauer amp Walker 2001 Perz et al 2006Alter 2007)

124 Vaccination and viral treatment

o date an active or passive vaccinationagainst HCV is not yet available Te main actorthat hampers the development o an efficient

vaccine is the considerable genetic heterogeneityo this positively-stranded RNA virus Howeverbetter understanding o the natural immunityto HCV and the proo o vaccine efficacy in the

chimpanzee challenge model allows some opti-mism about the development o an at least partlyeffective vaccine against this heterogeneouspathogen (Houghton amp Abrignani 2005)

In view o the act that the natural courseo chronic HCV inection is variable and thatthe currently established antiviral combinationtherapy with a pegylated intereron (PEG-IFN)and ribavirin (RBV) has numerous side-effectsthe decision to treat or not to treat must be deter-mined on an individual basis (Poynard et al 2003 Adhal 2004 Deutsch amp Hadziyannis 2008) Te main goal o antiviral therapy is asustained virological response defined as unde-tectable HCV RNA in serum 24 weeks aer theend o treatment determined with the mostsensitive PCR technique reatment regimensand responsiveness vary depending o the HCVgenotypes

In patients inected with genotype 1 or 4HCV eradication rates range between 45ndash52 In

contrast in patients inected with HCV genotype2 or 3 antiviral therapy results in HCV eradica-tion in 75ndash90 o cases Currently several novelantiviral agents are being evaluated in indi-

vidual studies eg NS3ndash4A protease inhibitorsRNA-dependent RNA polymerase inhibitorsand different immune therapies (Manns et al 2007)

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Hepatitis C virus

2 Cancer in Humans

Tis section ocuses on cohort and casendashcontrol studies published since the last IARC

Monograph (IARC 1994) Only those studiesthat used second- or third-generation assays todetermine HCV antibody status are examined Ia measure o relative risk (RR) was not providedby the authors the Working Group calculated acrude relative risk and 95 confidence intervals(CI) Only those studies in which a relative riskcould be specifically estimated were includedStudies that ocused specifically on the effecto the interaction o HCV and another actor(eg HBV) on the occurrence o hepatocellular

carcinoma (HCC) are addressed in the relevantsubsection

21 Hepatocellular carcinoma

In the previous IARC Monograph (IARC 1994) data on the relationship between inec-tion with HCV as indicated by the presence oantibodies to HCV (anti-HCV) were examinedin three cohort studies and over 20 casendashcontrol

studies Seropositivity or HCV antibodies wasmeasured by either first- or second-generationtests An increased risk or HCC was apparent inall three cohort studies Among the casendashcontrolstudies odds ratio (OR) estimates ranging rom13ndash134 were observed in 17 studies in whichfirst-generation tests were used and were statis-tically significant in 15 o the studies In six casendashcontrol studies that used second-generationassays the estimated odds ratios ranged rom11ndash52 and were significant in three studies In

the ew casendashcontrol studies in which the anal-ysis took into account possible conounding othe effects o HCV by other risk actors or HCCsuch as smoking and alcohol consumption theassociation with HCV was not materially altered

211 Cohort studies

able 21 (available at httpmonographsiarcrENGMonographsvol100B100B-03-able21pd ) provides a detailed summary o

the cohort studies that investigated the associa-tion o HCV with the development o HCC bygeographic area Cohort studies o patients withchronic liver diseasecirrhosis were excludeddue to the difficulties in interpreting the findingsrom such studies this exclusion is analogous tothat or casendashcontrol studies involving controlgroups comprising chronic liver disease patients

O the eight cohort studies considered sixwere conducted in Asia and one each in theAmericas and Australia O note the cohortstudy conducted in Australia (Amin et al2006) involved persons included in the NewSouth Wales Notifiable Diseases Database Anassociation between HCV seropositivity andHCC was observed in each o the eight cohortstudies with relative risks ranging rom 25ndash88Te effect estimate was statistically significantin all but one study (Yuan et al 1995) Potentialconounding by risk actors or HCC particu-larly inection with HBV was not addressed in

our o the studies (Yuan et al 1995 Boschi-Pinto et al 2000 Mori et al 2000 Guiltinanet al 2008) Te wide range in the relative risksreported most likely reflects variations across thestudy populations in the underlying prevalenceo HCV as well as in the duration o HCV inec-tion Only the study by Mori et al (2000) exam-ined the effect o anti-HCV titre and reported astronger association or a high anti-HCV titre(RR 404) than or a low antibody titre (RR 34)

212 Casendashcontrol studies

Details o the 18 casendashcontrol studiessummarized can be ound in able 22 (availableat httpmonographsiarcrENGMonographs

vol100B100B-03-able22pd ) A ew studieswere excluded based on the ollowing criteria less

141

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than 20 HCC cases were included in the studythe control group was comprised o patients withchronic liver disease or inormation related tothe comparability o case and control subjectswith respect to age and sex was not provided

Most o the casendashcontrol studies wereperormed either in Europe (n = 7) or Asia (n = 6)Te results rom all 18 studies both hospital-based and population-based support a carcino-genic role o HCV in the development o HCCTe adjusted odds ratios or anti-HCV seroposi-tivity ranged rom 28ndash170 eight studies reporteda more than 20-old increased risk o HCC (Park et al 1995 Shin et al 1996 anaka et al 1996sai et al 1996 De Vita et al 1998 agger

et al 1999 Kuper et al 2000 Yuan et al 2004)Potential conounding by risk actors or HCCparticularly inection with HBV was addressedin hal o these studies (see able 22 on-line)As with the cohort studies the wide range inthe observed odds ratios across the casendashcontrolstudies is likely to be related to the underlyingprevalence o HCV and duration o inection Inthose casendashcontrol studies in which the presenceo anti-HCV and HCV RNA was determined theobserved association was stronger or positivity

to both markers than or anti-HCV alone (Kew et al 1997 agger et al 1999 Gelatti et al 2005Franceschi et al 2006a)

213 Meta-analyses

wo meta-analyses have examined the inter-active effect o HBV and HCV inections on theoccurrence o HCC (see the Monograph on HBVin this volume) based on casendashcontrol studies(including casendashcontrol studies nested withincohorts) In both analyses estimates o theoverall association between HCV and HCC werealso provided Donato et al (1998) calculated asummary odds ratio or 21 studies publishedbetween 1992ndash97 using second-generation anti-HCV or HCV RNA assays Te overall odds ratioor HCV was 82 (95CI 67ndash99) Te estimate

was higher or studies in areas where HBV inec-tion is at low-to-intermediate endemicity andwhere HCV inection is predominant amongHCC cases (Japan and Mediterranean countriesOR 168 95CI 119ndash241) than or studies inareas where HBV inection is highly endemic(subSaharan and southern Arica aiwan(China) China Republic o Korea Viet NamOR 62 95CI 49ndash78) Te summary odds ratiowas also slightly higher or studies with commu-nity controls (OR 90 95CI 70ndash116) than orthose with hospital controls (OR 68 95CI51ndash91) In a similar analysis o 32 casendashcontrolstudies published in the Chinese literature Shi et al (2005) reported a summary odds ratio o 46

(95CI 36ndash59) or anti-HCVHCV RNA posi-tivity and HCC Te calculated odds ratio wassomewhat larger in higher HCC incidence areas(OR 53 95CI 38ndash74) than in lower incidenceareas (OR 38 95CI 28ndash52) Tere was littledifference in the estimates based on studies withcommunity controls or with hospital controls(OR 47 95CI 36ndash61 and OR 44 95CI29ndash66 respectively)

214 HCV genotype

able 23 (available at httpmonographsiarcrENGMonographsvol100B100B-03-able23pd ) summarizes the results rom ourcasendashcontrol studies and one community-basedcohort study in which the effect o HCV geno-type on HCC was examined wo casendashcontrolstudies in Japan reported significant increasedodds ratios or HCV genotype 1b compared toother genotypes among persons inected withHCV (anaka et al 1996 1998a) A weaker crudeassociation between Group 1 (1a 1b) inectionand HCC incidence was obtained rom the nestedcasendashcontrol study o HCC conducted within thecommunity-based own C HCV Study (Suruki et al 2006) Te Brescia HCC study examinedthe HCV genotype in the HCV RNA-positiveHCC cases and non-cancer patient controls

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Hepatitis C virus

(agger et al 1999) and reported a larger effectsize or genotype 1b inection (OR 342) thanor genotype 2 inection (OR 144) relative toanti-HCV seronegatives A comparison o HCVgenotypes 1b to 2 yielded an adjusted odds ratioo 29 (95CI 09ndash10) (Donato et al 1997) Incontrast an additional hospital-based study inItaly observed increased risks (27-old) o HCCor both genotype 1 and genotype 2 inectionscompared to anti-HCV seronegatives (Franceschi et al 2006a)

Seven cohort studies (Bruno et al 19972007 Naoumov et al 1997 Niederau et al 1998anaka et al 1998b Ikeda et al 2002 Imazeki et al 2003a Obika et al 2008) and two casendash

control studies (Hatzakis et al 1996 Silini et al 1996) have examined the association betweenHCV genotype and HCC among patients withHCV-related liver disease However uncertaintyabout HCV treatment in these patients as well aspotential bias related to their identification andinclusion as study subjects make the interpreta-tion o the findings rom such studies difficult

215 Cofactors modifying the risk of HCV-associated HCC

A brie summary o the findings rom studiesthat examined potential modifiers o the effecto HCV on the development o HCC is providedbelow and in able 24 (available at httpmono-graphsiarcrENGMonographsvol100B100B-03-able24pd ) Tose studies that evaluatedthe interaction o the actor with a combinedHCV andor HBV inection status were notconsidered

(a) Heavy alcohol consumption

Alcohol consumption has been classifiedby IARC as a human carcinogen with a role inthe etiology o liver cancer (IARC 1988 2010)A positive interaction on the additive scalebetween HCV and habitual alcohol drinking wasobserved in a community-based cohort study

in Japan (Mori et al 2000) o note only cruderelative risks could be calculated or this studySun et al (2003) also investigated the potentialsynergy o HCV inection with habitual alcoholdrinking in their cohort study in aiwan China(Sun et al 2003 Wang et al 2003) and no inter-action was observed in this low (20 prevalence)alcohol consumption population Te synergyindex obtained suggested that the combinedeffect o HCV and habitual alcohol drinking wasnot more than the additive effect o either actoralone A positive more than additive interactionbetween HCV and heavy alcohol consumptionwas reported in the hospital-based Brescia HCCcasendashcontrol study in Italy (Donato et al 2002)

However because alcohol-induced cirrhosis mayalter alcohol consumption beore the develop-ment o HCC the evaluation o alcohol in casendashcontrol studies can be problematic

(b) Smoking

IARC has also identified tobacco smoking asa liver carcinogen (IARC 2004) In the cohortstudies in Japan (Mori et al 2000) and aiwanChina (Sun et al 2003) a more than additiveeffect o anti-HCV seropositivity and cigarettesmoking on HCC incidence was suggested asnoted in the alcohol subsection above no adjust-ment or potential conounders was perormedin the Japanese study

(c) Diabetes mellitus

A meta-analysis o 26 studies (13 casendashcontrol studies and 13 cohort studies) publishedthrough February 2005 indicated that diabetesmellitus appears to be an independent risk actor

or HCC (El-Serag et al 2006) However noclear evidence with respect to a possible interac-tion between diabetes and HCV inection on therisk o HCC was ound based on a SurveillanceEpidemiology and End Results(SEER)-Medicaredatabase casendashcontrol study o HCC in theUnited States o America (Davila et al 2005)

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and a community-based cohort study in aiwanChina (Lai et al 2006)

(d) Betel quid chewing

wo studies in aiwan China examinedthe interaction between HCV and habitualbetel quid chewing (Sun et al 2003 sai et al 2001) Te study by Sun et al (2003) resulted ina synergy index o 42 suggestive o a greaterthan additive increased risk o HCC related tothe combined effect o HCV inection and betelquid chewing than o either actor alone Teinteraction appeared to be weaker in the studyby sai et al (2001) with a synergy index o 166the reported odds ratios were not adjusted or

potential conounders

(e) Human T-lymphotropic virus type 1 infection

A more than additive effect o human-lymphotropic virus type 1 (HLV-1) co-inec-tion on the association o HCV with liver cancerdeath was observed (RR 219 or HCV-positiveHLV-1-positive) in the Miyazaki Cohort Studyo an HLV-1 endemic population in Japan(Boschi-Pinto et al 2000)

(f) Radiation exposure

Te Radiation Effects Research FoundationLie Span Study by Sharp et al (2003) reporteda greater than multiplicative interaction or thecombined effect o HCV inection and radiationexposure in both the second (OR 551) and third(OR 287) tertiles

(g) Schistosoma infection

A casendashcontrol study conducted at the

National Cancer Institute in Egypt investigatedthe interaction between inection with HCVand inection with Schistosoma mansoni amongthe subjects negative or HBsAg (Hassan et al 2001) however no meaningul interaction wasobserved

(h) Helicobacter pylori infection

It has been hypothesized that Helicobacter species could play a role in the developmento HCC (Pellicano et al 2008) Several cross-

sectional studies have detected the presenceo Helicobacter in HCV-inected HCC cases(Ponzetto et al 2000 Pellicano et al 2004Rocha et al 2005)

216 Co-infection HCVHBV

See the Monograph on HBV in this volume

22 Cancers other than hepatocellular

carcinoma221 Biliary tractgallbladder

(a) Cohort studies

Te cohort study in Australia (Amin et al 2006) included in able 21 (on-line) also inves-tigated the effect o monoinection with HCV onthe incidence o gallbladder cancer however noincreased rate o the malignancy was observed(standardized incidence ratio [SIR] 05 95CI

01ndash20 based on 2 newly reported cases)(b) Casendashcontrol studies

able 25 (available at httpmonographsiarcrENGMonographsvol100B100B-03-able25pd ) summarizes the seven casendashcontrolstudies that have examined the association oHCV with cholangiocarcinoma and biliary tractcancers five o which were perormed in Asiancountries (Republic o Korea Japan and China)

In the Republic o Korea a hospital-based

study o 203 HCC cases (summarized in able 22on-line) also included 41 cases o cholangiocarci-noma without distinction o site and observeda positive association (OR 39 95CI09ndash171)o anti-HCV seropositivity with that malignancy(Shin et al 1996) Five casendashcontrol studiesprovided results with respect to the association

144

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Hepatitis C virus

between anti-HCV seropositivity and intrahe-patic cholangiocarcinoma Statistically signifi-cant odds ratios were observed in three o thosestudies (Donato et al 2001 Yamamoto et al 2004 Shaib et al 2007) with a more than 5-oldincreased risk o intrahepatic cholangiocar-cinoma related to HCV Te largest study (Lee et al 2008) which included 622 cases in theRepublic o Korea did not find any associationbetween anti-HCV positivity and intrahepaticcholangiocarcinoma (OR 10 95CI 05ndash19)o note the reported odds ratio was not adjustedor any potential conounders One study alsoincluded cases o extrahepatic cholangiocar-cinoma (Shaib et al 2007) but the association

between anti-HCV and this subtype was weakerand not statistically significant Not presentedin able 25 (on-line) is a casendashcontrol studybased on the SEER cancer registry and Medicareclaims data which determined HCV inectionstatus and case status using ICD-9 diagnosticcodes (Welzel et al 2007) In that study as wellthe effect was more pronounced or intrahepaticcholangiocarcinoma (adjusted OR 44 95CI14ndash140 n = 535 cases) than or extrahepaticcholangiocarcinoma (adjusted OR 15 95CI

02ndash110 n = 549 cases)Hsing et al (2008) conducted a casendashcontrol

study o incident biliary tract cancers in ShanghaiAn age-adjusted increased risk associated withanti-HCV seropositivity was not observed orcancer o either the gallbladder the extrahepaticbile ducts or the ampulla o Vater

222 Lymphoid malignancies

(a) Cohort studies

able 26 (available at httpmonographsiarcrENGMonographsvol100B100B-03-able26pd ) includes detailed descriptions oseven cohort studies that examined the effect oHCV inection on the occurrence o lymphoidmalignancies by the HIV status o the subjectsIn the five studies o HIV-negative subjects

three ound an approximately 2-old excess risko either non-Hodgkin lymphoma generally orB-cell non-Hodgkin lymphoma specificallyamong individuals who were inected with HCV(Ohsawa et al 1999 Duberg et al 2005 UlcickasYood et al 2007) Due to the small number ocases that occurred in all three cohorts the asso-ciation was statistically significant only in theSwedish study o B-cell non-Hodgkin lymphoma(Duberg et al 2005) Te Swedish study alsoobserved a similar but statistically non-signifi-cant effect o HCV inection on the developmento the chronic lymphocytic leukaemia subtype aswell as multiple myeloma A nested casendashcontrolstudy within a cohort o parents and offspring in

the USA did not detect HCV in any o the B-cellnon-Hodgkin lymphoma multiple myeloma orHodgkin disease cases or the matched controls(Rabkin et al 2002) A cohort study in Australiaalso reported no association o HCV with non-Hodgkin lymphoma nor with subtypes suchas ollicular lymphoma diffuse non-Hodgkinlymphoma and -cell non-Hodgkin lymphoma(Amin et al 2006) in addition an increasedrisk was not ound or either multiple myelomaor Hodgkin disease Not included in able 26

is a cohort study rom the USA which usedthe Department o Veterans Affairs admin-istrative patient databases with HCV statusand the occurrence o lymphoid malignanciesbased on ICD-9 CM diagnostic codes (Giordanoet al 2007) Te adjusted relative risks were 128(95CI 112ndash145) or non-Hodgkin lymphoma(n = 1359 cases) 089 (95CI 068ndash115) orchronic lymphocytic leukaemia (n = 412 cases)095 (95CI 076ndash119) or multiple myeloma

(n = 526 cases) and 097 (95CI 074ndash127) orHodgkin disease (n = 360 cases)For both cohort studies o HIV-positive

subjects a null association was observed betweenanti-HCV seropositivity and non-Hodgkinlymphoma (Waters et al 2005 Franceschi et al2006b)

145

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(b) Casendashcontrol studies

Tis section summarizes the casendashcontrolstudies included in the meta-analyses by Matsuo et al (2004) and Dal Maso amp Franceschi (2006)

Other casendashcontrol studies were considered i atleast 20 cases o lymphoma were investigated inthe study the control group was not comprisedo patients with other haematological malignan-cies andor lymphoprolierative diseases andinormation related to the comparability o caseand control subjects with respect to age and sexwas provided

Results related to a particular non-Hodgkinlymphoma subtype are included when datawere provided or ge 20 cases In addition to

B-cell non-Hodgkin lymphoma the subtypesevaluated were -cell non-Hodgkin lymphomadiffuse large B-cell lymphoma (DLBCL) olli-cular lymphoma marginal zone lymphoma andchronic lymphocytic leukaemiasmall lympho-cytic lymphoma (CLLSLL)

A large number o casendashcontrol studies haveexamined the association between HCV inec-tion and non-Hodgkin lymphoma Te detaileddescription o these studies and their findings

by geographic area are provided in able 27(available at httpmonographsiarcrENGMonographsvol100B100B-03-able27pd )Most studies were conducted in Europe(n = 20) ollowed by the Americas (n = 8) andAsia (n = 7) one study each was perormedin Arica and Australia B-cell non-Hodgkinlymphoma specifically andor non-Hodgkinlymphoma generally was the primary malig-nancy o interest in all 37 casendashcontrol studiesApproximately 80 o the studies reported at

least a 2-old increased risk o non-Hodgkinlymphoma or a B-cell non-Hodgkin lymphomawith HCV seropositivity Te association wasevident in casendashcontrol studies conducted acrossall geographic areas (except or the study inAustralia) and using different sources o controlgroups (ie hospital-based population-based

or blood donors) Odds ratios greater than 50were observed in 13 studies nine studies wererom Europe (Ferri et al 1994 Mazzaro et al 1996 Musto et al 1996 De Rosa et al 1997 De Vita et al 1998 Paydas et al 1999 Vallisa et al 1999 Zucca et al 2000 Yenice et al 2003) andour studies were rom elsewhere (Zuckerman et al 1997 Harakati et al 2000 Kuniyoshi etal 2001 Chindamo et al 2002) An additional 16casendashcontrol studies reported a 2ndash4-old excessrisk o either non-Hodgkin lymphoma or B-cellnon-Hodgkin lymphoma associated with HCVinection the effect was statistically significantin more than hal (Silvestri et al 1996 Mizorogi et al 2000 Montella et al 2001b Imai et al

2002 Mele et al 2003 Cowgill et al 2004Engels et al 2004 Iwata et al 2004 alamini et al 2004 Schoumlllkop et al 2008 Spinelli et al 2008) Te remaining eight casendashcontrol studieswith odds ratios less than 2 did not demon-strate a statistically significant effect o HCVon the occurrence o non-Hodgkin lymphomaor B-cell non-Hodgkin lymphoma (Kaya et al 2002 Avileacutes et al 2003 Morgensztern et al 2004 de Sanjoseacute et al 2004 Segraveve et al 2004Vajdic et al 2006 Sonmez et al 2007 Park et al

2008) Not included in able 27 is the SMAHR(SEER-Medicare Assessment o HepatopoieticMalignancy Risk raits) study a casendashcontrolstudy o haematopoietic malignancies based onthe use o the SEER-Medicare data in the USA(Anderson et al 2008) Cancer diagnosis as wellas HCV status was obtained rom the ICD codesincluded in the two databases Te adjustedodds ratio or the association o HCV with non-Hodgkin lymphoma overall (n = 33940 cases)

was 135 (95CI 11ndash17)Te findings o two pooled analyses are alsoincluded in able 27 One pooled study reportedan overall odds ratio o 15 (95CI 095ndash22) orB-cell lymphoma based on 1465 cases rom fiveEuropean countries (Nieters et al 2006) Teother pooled study ound a similar association(OR 18 95CI 14ndash23) or all non-Hodgkin

146

7232019 mono100B-8


Hepatitis C virus

lymphoma using 4784 cases rom seven studiesinvolving centres in the USA Canada Australiaand Europe (de Sanjoseacute et al 2008) Te latteranalysis included the results rom five previouslypublished studies (Engels et al 2004 Morton et al 2004 alamini et al 2004 Nieters et al 2006 Vajdic et al 2006)

In two casendashcontrol studies o non-Hodgkinlymphoma a slightly stronger associationwas ound or low-grade B-cell non-Hodgkinlymphoma in contrast to intermediatehigh-grade disease (Engels et al 2004 alamini et al 2004) Based on an a priori hypothesis that HCVwould be related to non-Hodgkin lymphoma atthe potential target organ o inection an early

study in Italy examined the effect o HCV onliversalivary gland non-Hodgkin lymphomaand reported a marked elevation in risk (OR515) (De Vita et al 1998)

With respect to other subtypes o non-Hodgkin lymphoma an effect o HCV inectionhas less consistently been observed Moreoverwhen an association is suggested the effect esti-mate usually is highly unstable due to the smallnumber o cases involved From the results o thestudies included in able 27 (on-line) an associa-

tion with HCV seems more evident or the DLBCLand CLLSLL subtypes For DLBCL results wereavailable rom 14 casendashcontrol studies 13 studiesobserved an association consistent with an effecto HCV seropositivity on DLBCL which wassignificant or about hal (Silvestri et al 1996Vallisa et al 1999 Zucca et al 2000 Chindamo et al 2002 Mele et al 2003 alamini et al 2004Spinelli et al 2008) Eight o the 12 studies thatexamined CLLSLL reported an odds ratio o at

least 2 with the association being statisticallysignificant in three casendashcontrol studies (Musto et al 1996 De Rosa et al 1997 Paydas et al 1999) For the ewer number o studies (n = 10)that included separate odds ratios or ollicularlymphoma and marginal zone lymphomaslightly more than hal reported an odds ratiogreater than 2 or HCV seropositivity (Silvestri

et al 1996 Vallisa et al 1999 Zucca et al 2000Mele et al 2003 Engels et al 2004 Spinelli et al2008) In contrast the findings rom almost allstudies did not support a notable effect o HCV on-cell non-Hodgkin lymphoma Te SMAHRstudy reported the ollowing odds ratios ornon-Hodgkin lymphoma subtypes 15 (95CI105ndash22) or DLBCL (n = 10144 cases) 22(95CI 12ndash395) or marginal zone lymphoma(n = 1908 cases) 19 (95CI 12ndash30) or ollicularlymphoma (n = 4491 cases) 11 (95CI 070ndash17)or chronic lymphocytic lymphoma (n = 10170cases) and 042 (95CI 010ndash17) or -cell non-Hodgkin lymphoma (n = 1870 cases) (Andersonet al 2008) In a pooled analysis (de Sanjoseacute

et al 2008) a statistically significant associationwas ound or DLBCL (OR 22 95CI 17ndash30)and marginal zone lymphoma (OR 25 95CI14ndash42) Te other pooled study (Nieters et al2006) also reported a significant association orDLBCL (OR 22 95CI 12ndash39) but no associa-tion was reported or marginal zone lymphomaTe effect o HCV was weaker and not statisti-cally significant or CLLSLL and not apparentor ollicular lymphoma or -cell lymphoma inboth pooled studies

O eight casendashcontrol studies that examinedmultiple myeloma (able 27 on-line) our studiesobserved a statistically significant associationbetween HCV seropositivity and the malignancy(Musto et al 1996 De Rosa et al 1997 Paydaset al 1999 Montella et al 2001a b) Te pooledanalysis by the EPILYMPH group (Nieters et al2006) did not report a notable association ormultiple myeloma (OR 14 95CI 061ndash32)

More than ten o the casendashcontrol studies

included in able 27 (on-line) conducted sepa-rate analyses o the effect o HCV on the occur-rence o Hodgkin disease An increased risk wasobserved in eight casendashcontrol studies althoughit was significant only in one study (Paydas et al1999) Te US record-based study by Andersonet al (2008) ound an odds ratio o 12 (95CI038ndash37) based on 1155 Hodgkin disease cases

147

7232019 mono100B-8



In the pooled analysis by Nieters et al (2006)no effect o HCV on Hodgkin disease was ound(OR 097 95CI 027ndash35)

(c) Meta-analyses

Several meta-analyses o the relation-ship between HCV and lymphoma have beenpublished (Gisbert et al 2003 Matsuo et al 2004 Negri et al 2004 Dal Maso amp Franceschi 2006) Matsuo et al (2004) perormed a meta-analysis o 23 casendashcontrol studies (includingnested casendashcontrol studies) published betweenJanuary 1990 and August 2003 Studies wereincluded i an odds ratio or a relative risk wascalculated ldquoby comparing the HCV-positive

category to the negative categoryrdquo and non-cancer controls and a second- or third-generationHCV antibody test were used A summary oddsratio o 57 (95CI 41ndash80) or non-Hodgkinlymphoma was obtained the association wassomewhat stronger or B-cell non-Hodgkinlymphoma (OR 50 95CI 36ndash71) than or-cell non-Hodgkin lymphoma (OR 25 95CI14ndash46) Te variation was related to the use oblood donor controls (OR 84 versus OR 465or non-blood donor controls) and to the yearo publication (ie lower OR or the more recentpublications) [Te Working Group noted thatthe relative risks obtained in this meta-analysismight be inflated by underadjustment particu-larly by age group]

In their meta-analysis Dal Maso amp Franceschi (2006) examined 15 casendashcontrol studies andthree cohort studies published up to July 2006Studies were eligible or inclusion based on theollowing criteria i the control group did not

include patients with other lymphoprolierativediseases i cases and controls were comparablewith respect to age and sex or age and sex weretaken into account in the analysis i second- orthird-generation anti-HCV assays were usedand i HIV-positive subjects were excludedOnly casendashcontrol studies with ge 100 cases wereincluded in the overall analyses o non-Hodgkin

lymphoma findings regarding specific non-Hodgkin lymphoma subtypes and otherlymphoid malignancies were shown when therewere ge 20 cases or that subtype Te sex- and age-adjusted meta-relative risk or all non-Hodgkinlymphoma was 25 (95CI 21ndash30) and wassimilar or casendashcontrol (RR 25 95CI 21ndash31)and cohort (RR 20 95CI 18ndash22) studies Teeffect o HCV on non-Hodgkin lymphoma wasestimated to be higher in those studies with ahigher HCV prevalence (ge 5) among controlsubjects (RR 30 95CI 24ndash375) than thosestudies with a lower prevalence (RR 19 95CI18ndash205) Te results were relatively consistentby geographic area (RR 27 in southern Europe

RR 26 in the USA RR 21 in the Republic oKoreaJapan RR 23 in other areas) and yearo publication (RR 29 beore 2003 RR 22during 2003 and aer) However the associationappeared to be somewhat weaker in studies usingpopulation-based control subjects (RR 19) thanin those using hospital-based controls (RR27) With respect to non-Hodgkin lymphomasubtypes the relative risks obtained were 265(95CI 19ndash37) or DLBCL 27 (95CI 22ndash34)or ollicular lymphoma 34 (95CI 24ndash49) or

marginal zone 165 (95CI 135ndash20) or CLLSLL and 15 (95CI 113ndash205) or -cell non-Hodgkin lymphoma In addition a summaryrelative risk was estimated or multiple myeloma(RR 16 95CI 069ndash36) as well as or Hodgkindisease (RR 15 95CI 10ndash21) O note themeta-analysis did not include the results romtwo recently conducted large casendashcontrolstudies o lymphoid malignancies the nation-wide study o the Danish and Swedish popula-

tions by Schoumlllkop et al (2008) and the pooledInterLymph study by de Sanjoseacute et al (2008)

(d) Treatment of HCV infection in patients withlymphoma

In a striking finding Hermine et al (2002) reported remission in seven o nine patients withsplenic lymphoma with villous lymphocytes who

148

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Hepatitis C virus

were inected with HCV aer they were treatedwith intereron α two more patients withouta substantial antiviral response experiencedremission aer the addition o ribavirin to inter-eron α None o six HCV-negative patients withsplenic lymphoma with villous lymphocytesresponded to intereron treatment A system-atic review by Gisbert et al (2005) reported onthe findings o 16 case reports and case series inwhich a total o 65 HCV-inected patients withlymphoprolierative disorders were treated withintereron α (with and without ribavirin) O the65 patients in those studies complete remissiono the disorder was achieved in 75 (95CI64ndash84) o the cases [Te Working Group noted

that one case series contributed almost a third othe patients analysed (n = 20) however the reer-ence was to an abstract or which a ull paper hasnot been published]

223 Other cancers

(a) Leukaemias

In the large cohort study o US veterans whowere inected with HCV a diagnosis o HCV wasnot related to an increased rate o acute lympho-

cytic leukaemia (RR 075) chronic myeloidleukaemia (RR 084) or acute non-lymphocyticleukaemia (RR 104) (Giordano et al 2007)

able 28 (available at httpmonographsiarcrENGMonographsvol100B100B-03-able28pd ) summarizes the our casendashcontrolstudies that investigated the effect o HCV inec-tion on the development o leukaemia No studyreported statistically significant associationsbetween anti-HCV seropositivity and acute

myeloid leukaemia acute lymphocytic leukaemiaor chronic myeloid leukaemia However Bianco et al (2004) suggested that HCV inection mightbe associated with both acute myeloid leukaemiaand chronic myeloid leukaemia in the Italianstudy In Japan Murashige et al (2005) reportedno association o anti-HCV seropositivity withthe risk o myeloid malignancy

(b) Cancer of the thyroid

Te three cohort studies in Sweden (Duberget al 2005) Australia (Amin et al 2006) and theUSA (Giordano et al 2007) examined the inci-

dence o thyroid cancers among people who wereinected with HCV A non-significant increasedrisk was ound based on five thyroid cancer casesin the Swedish cohort (SIR 155 95CI 050ndash36) whereas a significant decreased risk wasreported based on nine cases in the Australiancohort (SIR 03 95CI 02ndash07) and 46 casesin the US cohort (HR 072 95CI 052ndash099)A casendashcontrol study o a group o cancers inItaly (Montella et al 2001a) observed a signifi-cant association between HCV inection and this

malignancy (OR 28 95CI 12ndash63)

3 Cancer in Experimental Animals

In this Volume the Working Group decidednot to include a separate section on ldquoCancer inExperimental Animalsrdquo in the Monographs on

viruses but rather to include description o suchstudies under Section 4 (below) Te reasoning

or this decision is explained in the GeneralRemarks

4 Other Relevant Data

Te sharp increase o HCC cases over thelast several decades in industrialized countries(western Europe North America and Japan) hasbeen attributed to an expansion o chronic HCVinections and is requently linked with livercirrhosis Most cohort studies and clinical expe-rience have shown that liver fibrosis resultingrom long-lasting chronic inflammation is likelyto be an important predisposing actor o HCCdevelopment Te same clinical observations alsosuggest that ongoing liver regeneration resultingrom chronic immune mediated hepatocyte

149

7232019 mono100B-8



death is a likely actor contributing to the devel-opment o HCC (Liang amp Heller 2004) Tisaspect has been developed in the Monograph onHBV in this volume

But the mechanisms underlying the progres-sion o HCV inection to liver cancer whichoen takes many decades remain ill-definedranscriptomics and proteomics have helped toidentiy many genetic and epigenetic alterationsassociated with HCC clusters However the iden-tified changes to gene expression patterns are

very heterogeneous in tumour cells raising thequestion as to whether yet unidentified specificchanges at early preneoplastic stages triggerthe transormation process and what cell type

could be at the origin o HCC (Sell amp Leffert 2008) HCV has an exclusively cytoplasmiclie cycle (Lindenbach et al 2007 Moradpour et al 2007) and thereore HCV replication andpotentially pro-oncogenic events are restrictedto the cytoplasm While HCV inection leadsto chronic inflammation steatosis fibrosis andoxidative chromosomal DNA damage severalHCV proteins have been shown to have directoncogenic effects and to upregulate mitogenicprocesses (Koike 2007 McGivern amp Lemon

2009) Te accumulation o DNA damage withina setting o restricted cell-cycle checkpointcontrols is thought to compromise gene andchromosome stability and to orm the genomicbasis or the malignant phenotype

One o the major challenges with the studyo the carcinogenic role o HCV is the difficultyto localize the HCV genome and viral proteinsin both the liver o inected patients and livertumours

41 Biochemical properties of HCVproteins

See able 41

411 The structural proteins

(a) Core protein

Te core protein is the most conservedamong the structural proteins It is highly basicrich in proline and multimerizes Interactiono the mature core with the 5prime and 3prime NCRs canrespectively inhibit IRES unction and mediategenome dimerization (Shimoike et al 1999Cristoari et al 2004) Te core protein is targetedto the cytoplasmic surace o the endoplasmicreticulum and lipid droplets (Moradpour et al 1996 Barba et al 1997) Its interaction with lipiddroplets may be related to the increased inci-dence o liver steatosis in patients with HCV and

in certain transgenic mice that overexpress HCVcore (Moriya et al 1997a Barbaro et al 1999)It has also been shown that core can localize tomitochondrial outer membranes (Schwer et al 2004)

(b) HCV glycoproteins

Te HCV glycoproteins E1 (30 kDa) and E2(70 kDa) are type I transmembrane glycopro-teins that associate into non-covalently attachedheterodimers and mediate HCV cell entry and

membrane usion (Bartosch amp Cosset 2006Lavillette et al 2006 Lindenbach et al 2007)

412 The non-structural proteins

(a) p7

p7 is a small 7 kDa hydrophobic proteinpredicted to span the membrane twice withendoplasmic-reticulum-lumenal N - andC -terminals and a short positively charged cyto-

plasmic loop Te localization o p7 is not yetclear but overexpression o an epitope-tagged p7has been localized to the endoplasmic reticulumand mitochondria (Griffin et al 2005) Te p7protein is essential or virus assembly and releasein vitro (Steinmann et al 2007) and inectivityin vivo (Sakai et al 2003)

150

7232019 mono100B-8


Hepatitis C virus

(b) NS2

NS2 is a 23 kDa membrane-spanning proteinwith a C -terminal cysteine protease activity thatcleaves the NS23 junction (Grakoui et al 1993Lorenz et al 2006) NS2 is urthermore requiredor viral assembly Its N -terminal domain mayinteract with the structural proteins and p7whereas downstream sequences may interactwith other NS proteins (Lindenbach et al 2007

Jirasko et al 2008)

(c) NS3

HCV NS3 is a 70 kDa multiunctional proteincontaining an N -terminal serine proteasedomain and a C -terminal RNA helicaseNPasedomain that unwinds double-stranded nucleic

acids (Lindenbach et al 2007) Although theprecise role o the NS3 helicase is not yet knownhelicase activity has been shown to be essentialor HCV RNA replication and viral inectivity(Lam amp Frick 2006)

(d) NS4A

NS4A is an 8 kDa protein with multiple unc-tions in the virus lie cycle It is a coactor that

assists in the correct olding o the serine proteaseand acilitates recognition o RNA substrates bythe NS3 proteasehelicase (Pang et al 2002)NS4A can physically interact with NS4B andNS5A and uncleaved NS4B-5A to promote NS5Ahyperphosphorylation (Lindenbach et al 2007and reerences therein)

151

Table 41 HCV proteins their role in the viral life cycle and putative role in hepatocytetransformation

HCV proteins Role in viral life cycle Potential role in cellular transformation (examples)

Core protein Nucleocapsid assembly Insulin resistancesteatosisIntererence (direct or indirect) with p53 p73 pRb

Intererence with host cel l signall ing (NF-κB Wntβ-catenin pathway)

Intererence with GF-β signalling

ranscriptional activation o cellular genes

Apoptosis

E1E2 glycoprotein Virus morphogenesis Intererence with the intereron-inducible proteinkinase (PKR) activity

Cell entry

p7 Virus assembly export and inectivity

NS2 Polyprotein processing and Viral assembly Inhibition o apoptosis

NS3 N -terminal domain Serine protease activity Intererence with hepatocyte innate response

NS3 C -terminal domain Helicase activity

HCV genome replication

NS4A Co-actor o NS4B and NS5A Induction o ER stress

NS4B Formation o membranous web structures

NS5A Part o the replication complex Inhibition o the intereron-inducible PKR

Oxydative stress

Activation o cell signalling pathways (SA-3 NF-κBetc)

Accumulation o β-catenin by indirect mechanism

NS5B RNA-dependent RNA polymerase

ER endoplasmic reticulum PKR double-stranded RNA-activated protein k inase

Compiled by the Working Group

7232019 mono100B-8



(e) NS4B

NS4B is a 27 kDa integral membrane proteincontaining our central transmembrane domainswith yet unclear topology Its expression is suffi-

cient to induce the ormation o lsquomembraneouswebrsquo structures that contain the membrane-bound replication complex (Egger et al 2002Gosert et al 2003) and it encodes a GPaseactivity that seems to be critical or RNA repli-cation (Einav et al 2004)

(f) NS5A

NS5A is a 58 kDa phosphoprotein with animportant yet unclear role in RNA replication(Shimakami et al 2004) It localizes to activereplication complexes (Gosert et al 2003Moradpour et al 2004) interacts with NS5B andinhibits its RNA polymerase activity (Shirota et al 2002 Dimitrova et al 2003)

(g) NS5B

NS5B is a 68 kDa endoplasmic-retic-ulum-membrane-associated protein withRNA-dependent polymerase activity Mutationsthat interere with its membrane association

destroy RNA replication Intramolecular interac-tions as well as oligomerization o NS5B stimulateRNA synthesis and the NS3 helicase enhancesprimed RNA synthesis activity in contrast toNS4B and NS5A which inhibit RNA synthesis(Lindenbach et al 2007 and reerences therein)NS5B has been and remains a major target or thedevelopment o HCV-specific drugs at the timeo writing drug research and development isocusing on cellular coactors o NS5B the cyclo-philins Te unction o NS5B has been shown to

be upregulated by cyclophilin B which in turn isregulated and thus sensitive to the immunosup-pressant ciclosporin A Compounds belongingto this amily are currently investigated or theirantiviral efficacy (Watashi et al 2005 Watashi amp Shimotohno 2007)

42 Biological properties of HCVproteins

See able 41

[Te Working Group noted that besides thecomplex interactions among themselves the viral proteins interact with a significant numbero host actors and signalling pathways that maycontribute to the pathological consequences oHCV inection Tese interactions interere withinnate immunity and thus contribute to persis-tence o inection and inflammation but theyhave also been described to modulate transcrip-tion translation and post-translational events toalter cell signalling apoptosis membrane physi-

ology and trafficking Furthermore they caninduce oxidative stress genomic instability andpossibly cellular transormation

Many studies o the potential role o viralproteins in hepatocyte transormation have beenperormed in experimental models that are basedon the overexpression o viral proteins aer tran-sient transection o already transormed hepat-ocytes (such as HepG2 or Huh7 cells) Tesestudies show the interaction o viral proteinswith cellular partners that may be involvedin cellular transormation However becausethe expression o these viral proteins has beendifficult to demonstrate in liver tumours a linkbetween these in vitro observations and their invivo relevance in inected humans still needs tobe established Because o the lack o relevantmodels or mechanistic studies o HCV-inducedHCC the results o the major molecular studieshave been described below to provide an over-

view o the current hypotheses]

O the HCV gene products core NS3 NS4Band NS5A have all been shown to exhibit trans-ormation potential when transiently or stablyexpressed in tissue culture or in the context otransgenic mice carrying the single viral proteinsor an HCV polyprotein (Sakamuro et al 1995Ray et al 1996 Gale et al 1999 Park et al 2000)

152

7232019 mono100B-8


Hepatitis C virus

However many o the data below need to besubstantiated in the context o a viral inection


(a) Core protein

Core has been implied in changes o host cellsignalling transcriptional activation apoptosislipid metabolism and transormation Amongan impressive list o interactions with cellularactors core has been shown to physically andunctionally interact with p53 (Ray et al 1997Lu et al 1999) and p73 (Alisi et al 2003) andto decrease the expression o pRb (Cho et al 2001) tumour-suppressor proteins For instance

it was shown that HCV core co-immunoprecip-itates with p73 in HepG2 and SAOS-2 cells Tisinteraction results in the nuclear translocationo HCV core protein In addition the interac-tion with HCV core protein prevents p73-α-but not p73-β-dependent cell growth arrest ina p53-dependent manner Te results suggestedthat HCV core protein may directly influencethe various p73 unctions thus playing a role inHCV pathogenesis (Alisi et al 2003)

Core also modulates the expression o the

cyclin-dependent kinase (CDK) inhibitor p21Wa in a p53-independent manner (Kwun amp Jang 2003) p21 a well known transcriptionaltarget o p53 blocks activities o cyclinCDKcomplexes involved in cell-cycle control andtumour ormation

Core induces activation o the Ra1mitogen-activated protein kinase (MAPK) pathway (Aoki et al 2000 Hayashi et al 2000) relieves cellsrom serum starvation and growth arrest and

avours cell prolierationConflicting reports have shown both activa-tion (Ray et al 2002) and repression (Joo et al 2005) o the NF-κB pathways by HCV core

HCV core has been shown to activate theWntβ-catenin pathway which is implicated incell prolieration DNA synthesis and cell-cycleprogression (Fukutomi et al 2005)

Furthermore core variants isolated romliver tumours but not those isolated rom adja-cent non-tumourous liver have been shownto interact with Smad3 and inhibit the GF-βpathway (Pavio et al 2005) GF-β-signallingnot only controls cell prolieration differentiationand apoptosis but also stimulates liver regenera-tion and fibrogenesis through its actions on theextracellular matrix GF-β levels are requentlyincreased in chronic HCV patients and correlatewith the degree o fibrosis (Nelson et al 1997Marcellin et al 2002)

Finally HCV core protein associates withcellular membranes (Barba et al 1997 Moriyaet al 1997a) and lipid vesicles (Moriya et al

1997a) binds to apolipoprotein II and reducesmicrosomal triglyceride transer protein (MP)activity (Perlemuteret al 2002) leading to deectsin the assembly and secretion o vLDL and stea-tosis which in turn induces oxidative stress Tein vivo relevance o this interaction is supportedby the development o steatosis (Moriya et al1997b Perlemuter et al 2002) and liver cancer(Moriya et al 2001 Lerat et al 2002) in trans-genic mice expressing HCV core

(b) E2Overexpression o E2 inhibits eIF2α phos-

phorylation by the dsRNA-activated proteinkinase (PKR) or the endoplasmic-reticulum-stress signalling kinase PERK E2 also physicallyinteracts with PKR the E2PKR interaction mayaccount or the intrinsic intereronrsquos resistance oHCV genotypes 1a and 1b (aylor et al 1999Pavio et al 2003)

422 The non-structural proteins(a) NS4A NS4B or NS4A-4B

Overexpression o NS4A NS4B or NS4A-4Bhas been reported to induce an endoplasmic-reticulumstress-mediated unolded proteinresponse reduce endoplasmic-reticulum-to-Golgi traffic inhibit protein synthesis and to

153

7232019 mono100B-8



cause cytopathic effects (Lindenbach et al 2007and reerences therein)

(b) NS2

NS2 interacts with the cellular proapoptoticmolecule CIDE-B and inhibits CIDE-B-inducedapoptosis (Erdtmann et al 2003) NS2 has alsobeen shown to downregulate the transcriptiono several cellular and viral promoters in gene-reporter assays (Dumoulin et al 2003)

(c) NS3-4A

NS3-4A serine protease has been reported toblock the activation o the transcription actorsIRF-3 and NF-κB and to antagonize innate anti-

viral deenses by interering with the cytosolicRNA helicases RIG-1- and MDA5- and LR3-mediated signal transduction (Lindenbach et al 2007)

(d) NS5A

NS5A has multiple unctions It has beenshown to interact with the geranylgeranylatedcellular protein FBL2 (Wang et al 2005) anF-box-moti-containing protein that is likelyto be involved in targeting cellular proteins oyet unknown identity or ubiquitylation anddegradation

Several studies suggest that NS5A is alsoinvolved in the resistance to intereron treatment(Lindenbach et al 2007 and reerences therein)and one possible mechanism may be its abilityto induce expression o the type I intereronantagonist IL-8 (Polyak et al 2001) In additionNS5A contains an lsquointereron sensitivity deter-mining regionrsquo (ISDR) that mediates inhibition

o PKR an activator o innate immunity accu-mulation o mutations in this region is thoughtto correlate with treatment efficacy (Enomoto et al 1995 1996)

Overexpression o NS5A has been reported toinduce several effects in cells including oxida-tive stress activation o signalling pathways

including SA-3 PI3K and NF-κB (Gong et al 2001 He et al 2002 Street et al 2004)and degradation o pRB (Munakata et al 2005)

Other reported NS5A interaction partnersinclude apolipoprotein A1 the major proteinound on High Density Lipoprotein (HDL)the tumour suppressor p53 Grb-2 an adaptorprotein involved in mitogen signalling SRCAPan adenosine triphosphatase (APase) that acti-

vates cellular transcription karyopherin β3 aprotein involved in nuclear trafficking Cdk12cyclin-dependent and Fyn Hck Lck and LynSrc-amily kinases (Lindenbach et al 2007 andreerences therein)

More recently it has been reported that NS5A-

expression in the context o HCV polyproteinresults in the inhibition o the transcription actorForkhead as well as in the phosphorylation andinactivation o the GSK-3 leading to the accu-mulation o β-catenin and to the stimulation oβ-catenin-dependent transcription (Street et al 2005)

[Te Working Group noted that so arthe biological unctions o the HCV proteinshave been investigated in vitro or in vivo usingtransgenic mice constitutively expressing HCV

proteins alone in combination or the entirepolyprotein Whether the results generated bythese experimental approaches reflect the patho-logical consequences o an HCV inection in vivo remains to be addressed and this issue will onlybe resolved with the establishment o immuno-competent mouse models or other more physi-ological cellular models that permit chronic andproductive HCV replication]

154

7232019 mono100B-8


Hepatitis C virus

43 Experimental evidence for a roleof HCV in malignant conversion

431 Role of HCV chronic infection in HCC

development Successul clearance o chronic HCV inec-

tion has been shown to reduce the overall liver-related mortality and the incidence o HCCproviding urther evidence or a causal role oHCV in this cancer (Kasahara et al 1998 Seraty et al 1998 Imazeki et al 2003b)

Although chronic HCV inection is onemajor risk actor or HCC the mechanismsby which HCV induces HCC remain uncer-

tain (Levrero 2006 McGivern amp Lemon 2009) Chronic endoplasmic reticulum stressand inflammatory responses and the associ-ated oxidative stress and altered intracellularredox state lead to the accumulation o genomicdamage Tese are likely to contribute to andpredispose inected cells to hepatocarcinogen-esis possibly via changes in MAPK signallingthat regulates both cell metabolism and growth(ardi et al 2002 Waris et al 2007) Markerso intracellular oxidative stress have indeed been

reported to be increased in chronic HCV patients(Shimoda et al 1994 Sumida et al 2000) as wellas in HCV core transgenic mice (Moriya et al 1998 Moriya et al 2001) However in additiondirect interactions o the various HCV proteinswith host actors correlate with changes incellular signalling cascades that are involved inthe regulation o cell metabolism and divisionTe expression o some HCV proteins seem to besufficient to induce hepatocarcinogenesis at leastin some specific transgenic mice lineages such astransgenic C57BL6 mice (Lerat et al 2002) livertumour development was shown to be associatedwith HCV-induced liver steatosis (Lerat et al 2002 Moriya et al 1998)

Overall because o the lack o an experimentalmodel that replicates the viral lie cycle andnatural history o the disease the current view is

that synergistic effects between the consequenceso chronic inflammation and direct virusndashhostcell interactions are most likely Such synergisticeffects would also explain the long lsquomultisteprsquotransormation process in human HCC whichis consistent with the long time lag with whichcirrhosis and HCC maniest themselves uponchronic inection and would explain the wide

variety o genetic deects observed in individualHCCs (Torgeirsson amp Grisham 2002 Levrero2006 McGivern amp Lemon 2009)

Prospective and retrospective cohort studieso patients with chronic HCV inection havedemonstrated a role or the long duration othe disease in HCC development and the link

between HCC development and liver cirrhosisTese studies showed the sequential occurrenceo advanced liver fibrosis ollowed by the devel-opment o HCC Te incidence o HCC devel-opment was estimated to be between 3ndash5yearin cirrhotic patients (sukuma et al 1993 onget al 1995 Fattovich et al 1997)

432 Role of HCV-induced steatosis insulinresistance and oxidative stress in HCC

development Pro-carcinogenic coactors in chronic HCV

inection are steatosis oxidative stress andinsulin resistance suggesting many parallelswith non-alcoholic atty liver disease (NAFLD)In NAFLD chronic excess o nutrients causesendoplasmic reticulum stress and leads to anincrease o hepatic at (steatosis) and insulinresistance a complex interplay between theseactors can lead to chronic liver inflammationapoptosis and fibrogenesis which are thoughtto orm the prelude to liver cirrhosis and cancer(Hotamisligil 2006)

An increased prevalence o steatosis andinsulin resistance in HCV patients is well estab-lished and has prognostic implications as it isassociated with aster progression o fibrosis anda poorer response to treatment In HCV patients

155

7232019 mono100B-8



inected with genotypes 1 and 2 steatosispresents in general with concomitant obesity orother eatures o the metabolic syndrome butthis association is weak in genotype 3 patientsGenotype 3 is thought to induce steatosis in adirect ashion as steatosis in these patients corre-lates with viral load and reverses with responseto treatment (Negro 2006) HCV is thoughtto induce steatosis by impairing secretion anddegradation and increasing the neosynthesiso lipids Te HCV core protein which localizesto the surace o lipid droplets and mediates the

viral assembly in close conjunction with cellularatty acid metabolism (Miyanari et al 2007) andalso some HCV non-structural proteins have

all been shown to interere with vLDL secretion(Wetterau et al 1997 Domitrovich et al 2005)HCV inection has also been associated with anupregulation o the neosynthesis o lipids (Waris et al 2007) inhibition o atty acid oxidation(Dharancy et al 2005) and increased release oatty acids rom at cells (Negro 2006) Overallthe effects o HCV proteins on lipid synthesissecretion and oxidation seem to be most potentin the context o genotype 3 but also occur in thecontext o other genotypes

Te development o severe steatosis and HCCwas shown in PPARalpha-homozygous mice withliver-specific transgenic expression o the coreprotein gene while tumours were not observedin the other transgenic mouse genotypes Tisresult suggested that persistent activation oPPARalpha a central regulator o triglyceridehomeostasis is essential or the pathogenesiso hepatic steatosis and HCC induced by HCVinection (anaka et al 2008)

Besides changes in the lipid metabolism coreand several o the non-structural HCV proteinsinduce systemic oxidative stress and relatedsignalling by various mechanisms (ardi et al 2005)

With respect to insulin resistance all HCVgenotypes have been shown to interere withglucose homeostasis oen at early stages o

inection (Negro 2006) but the underlyingmechanisms and the degree o insulin resistanceseem to be again genotype-dependent HCV hasbeen shown to interere with insulin signalling byproteasomal degradation o the insulin receptorsubstrates (IRS)-1 and minus2 (Aytug et al 2003)

Te eedback circle between steatosis insulinresistance and oxidative stress is an importantdenominator or disease progression in NAFLD aswell as viral hepatitis and induces tissue damageand inflammation and consequently activationo hepatic stellate cells (HSCs) Activated HSCsbecome responsive to both prolierative andfibrogenic cytokines and undergo epithelial-to-mesenchymal transdifferentiation (EM) into

contractile myofibroblast-like cells that synthe-size extracellular matrix (ECM) componentswhich accumulate over time to orm fibrousscars or lsquofibrosisrsquo Ultimately nodules o regener-ating hepatocytes become enclosed by scar tissuewhich defines cirrhosis Activation o HSCs isregulated by products and effectors o oxidativestress and growth actors cytokines adipokinesand chemokines Te cytokine GF-β a potentinhibitor o epithelial cell growth and tumoursuppressor can also exert pro-oncogenic unc-

tions and is a key regulator o EM Importantlyrecent findings imply that GF-β induces EMnot only in HSCs but possibly also in hepato-cytes (Matsuzaki et al 2007) GF-β signallingis upregulated in fibrotic HCV patients andstimulates ECM deposition and accumulationInsulin resistance may link fibrosis and steatosisas it stimulates HSCs to deposit ECM Severalsignalling cascades are implicated and modu-lated during fibrogenesis including SMADs

PI3K-Akt and various MAPK pathways suchas p38 and JNK While SMADS are indispen-sable or the EM process GF-β signalling

via SMAD synergizes with other signallingpathways to mediate pro-oncogenic EMs JNKactivation by the pro-inflammatory cytokineinterleukin-1β can shi GF-β signalling awayrom a tumour-suppressive to a pro-oncogenic

156

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Hepatitis C virus

profile with augmented fibrogenesis increasedcell motility and transactivation o cell cycleregulatory genes (Matsuzaki et al 2007)Tus in the context o chronic inflammationthe interplay between endoplasmic reticulumoxidative stress steatosis and insulin resistanceinduces a pro-oncogenic microenvironment thatdrives fibrogenic processes and genomic insta-bility and even though HCV has been reportedto display direct transorming capacities theliver microenvironment is thought to determinesignificantly the transormation process becauseHCC develops in chronic HCV inection onlyover long periods o time

So ar it has not been possible to correlate

hepatocarcinogenesis with a consistent patterno proto-oncogene activation but several growthactor signalling axes are requently ound to bedysregulated including insulin-growth actor(IGF) hepatocyte growth actor Wnt GF-αEGF and GF-β signalling (Breuhahn et al 2006 Levrero 2006) Te interplay betweenthese various pathways and their respective rolesand contributions to the development o HCCremain to be unravelled

433 Role of HCV in lymphomas and othertumours

Te mechanisms by which lymphoma isinduced by HCV remains the subject o debateSeveral clinical studies have shown that the HCVgenome may be detected in peripheral lymphoidcells as well as dendritic cells (Bain et al 2001)However evidence o true viral genome replica-tion in extrahepatic sites is still lacking

Some early studies showed that HCV mayinect cultured peripheral blood mononuclearcells in vitro (Shimizu et al 1998) but theseobservations were not confirmed by other groups

Few studies showed that the HCV genomesequence rom extrahepatic isolates maycluster differently rom liver isolates providing

indirect evidence or viral replication in thesecells (Roque-Aonso et al 2005)

Clinical studies have shown that HCV eradi-cation by pegylated intereron and ribavirintreatment may lead to the cure o cryoglobu-linemia a B-cell prolieration disorder and to theregression o HCV-associated splenic lymphoma(Hermine et al 2002)

Several non-exclusive hypotheses have beendiscussed regarding the transorming role oHCV in the context o lymphoma 1) antigen-driven prolieration induced by continuousactivation o B cells (Suarez et al 2006) 2) adirect role o HCV replication and expression ininected B cells

Further molecular and cellular biologystudies are warranted to decipher the mecha-nisms o HCV-induced lymphomas

Regarding the role o HCV in the developmento cholangiocarcinoma both clinical evidenceand strong experimental data are lacking

44 Interaction between HCV andenvironmental agents

Regarding interactions between HBV andHCV please reer to the Monograph on HBV inthis volume

45 Animal models for HCV-associated cancers

Chimpanzees and tree shrews do not or onlypartially develop HCV-associated pathologiesupon inection And given the long delay withwhich HCC develops in chronic hepatitis thesemodels are unsuitable to study HCV-inducedHCC in the first place In the absence o animalmodels that develop HCC in the context o anHCV inection various groups have describedthe use o mouse models Mice expressingHCV replicons polyproteins or the single HCVproteins alone or in combination using various

157

7232019 mono100B-8



liver specific promoters have been describedby many groups (Levrero 2006 McGivern amp Lemon 2009)

o date studies using transgenic animalsexpressing HCV cDNA suggest that HCV proteinsare not directly cytopathic (Kawamura et al 1997 Pasquinelli et al 1997 Wakita et al 1998)Only three different HCV core transgenic lineshave been shown to develop liver steatosis andHCC (Moriya et al 1998 2001) and one grouphas been able to demonstrate that upon HCVpolyprotein expression the rate o liver cancer intransgenic mice increases in the absence o intra-hepatic inflammation suggesting a metabolic orgenetic host susceptibility or HCV-associated

HCC (Lerat et al 2002)NS5A transgenic mice despite the abundant

interactions o NS5A with host-cell actors donot have any significant phenotype (Majumder et al 2002 2003)

46 HCV host immune system andgenetic susceptibility

While many studies have been reportedregarding the role o the humoral and cellularresponses in the control o HCV inection aswell as micro-array analysis o primary livertumours showing differential expression o manycellular genes in the tumours no relevant dataare available at the time o writing concerningspecific immune or genetic mechanism involvedin HCV-induced HCC

47 Synthesis

Although there is strong evidence that HCVis one o the leading causes o HCC there isstill much to understand regarding the mecha-nism o HCV-induced transormation Whileliver fibrosis resulting rom long-lasting chronicinflammation and liver regeneration resultingrom immune-mediated cell death are likely

actors contributing to the development o HCCthe direct role o HCV proteins remains to bedetermined Many in vitro studies have shownthat HCV expression may interere with cellularunctions that are important or cell differentia-tion and cell growth However most studies wereperormed in artificial study models which canonly give clues or potential mechanisms thatneed to be confirmed in more relevant modelsFurthermore the difficulty to localize HCVproteins as well as inected cells in vivo in the livero inected patients contribute to the complexityo our current understanding

For all these reasons at the time o writingthe current view is that there is moderate experi-

mental evidence or a direct oncogenic role oHCV Further studies are warranted to clariythese issues

5 Evaluation

Tere is sufficient evidence in humans or thecarcinogenicity o chronic inection with HCVChronic inection with HCV causes hepatocel-lular carcinoma and non-Hodgkin lymphoma

Also a positive association has been observedbetween chronic inection with HCV andcholangiocarcinoma

Chronic inection with HCV is carcinogenicto humans (Group 1)

References

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Ali S Pellerin C Lamarre D Kukolj G (2004) Hepatitis C virus subgenomic replicons in the human embryonic kidney 293 cell line J Virol 78 491ndash501 doi101128JVI781491-5012004 PMID14671129

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7232019 mono100B-8


Hepatitis C virus

Alisi A Giambartolomei S Cupelli F et al (2003) Physicaland unctional interaction between HCV core proteinand the different p73 isoorms Oncogene 22 2573ndash2580 doi101038sjonc1206333 PMID12730672

Alter MJ (2002) Prevention o spread o hepatitisC Hepatology 36 Suppl 1S93ndashS98 doi101002

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Amin J Dore GJ OrsquoConnell DL et al (2006) Cancer inci-dence in people with hepatitis B or C inection a largecommunity-based linkage study J Hepatol 45 197ndash203doi101016jjhep200602014 PMID16684579

Anderson LA Peiffer R Warren JL et al (2008)Hematopoietic malignancies associated with viral andalcoholic hepatitis Cancer Epidemiol Biomarkers Prev 17 3069ndash3075 doi1011581055-9965EPI-08-0408 PMID18957521

Andreacute P Perlemuter G Budkowska A et al (2005)Hepatitis C virus particles and lipoprotein metabolismSemin Liver Dis 25 93ndash104 doi101055s-2005-864785 PMID15732001

Aoki H Hayashi J Moriyama M et al (2000) HepatitisC virus core protein interacts with 14ndash3-3 proteinand activates the kinase Ra-1 J Virol 74 1736ndash1741doi101128JVI7441736-17412000 PMID10644344

Avileacutes A Valdez L Halabe J et al (2003) No associationbetween lymphoma and hepatitis C virus Med Oncol 20 165ndash168 doi101385MO202165 PMID12835519

Aytug S Reich D Sapiro LE et al (2003) Impaired IRS-1PI3-kinase signaling in patients with HCV a mecha-nism or increased prevalence o type 2 diabetes

Hepatology 38 1384ndash1392 PMID14647049Bain C Fatmi A Zoulim F et al (2001) Impaired

allostimulatory unction o dendritic cells in chronichepatitis C inection Gastroenterology 120 512ndash524doi101053gast200121212 PMID11159892

Barba G Harper F Harada et al (1997) Hepatitis C viruscore protein shows a cytoplasmic localization and asso-ciates to cellular lipid storage droplets Proc Natl AcadSci USA 94 1200ndash1205 doi101073pnas9441200 PMID9037030

Barbaro G Di Lorenzo G Asti A et al (1999) Hepatocellularmitochondrial alterations in patients with chronichepatitis C ultrastructural and biochemical findings

Am J Gastroenterol 94 2198ndash2205 doi101111j1572-0241199901294x PMID10445550Bartosch B amp Cosset FL (2006) Cell entry o hepa-

titis C virus Virology 348 1ndash12 doi101016j virol200512027 PMID16455127

Bianco E Marcucci F Mele A et alItalian Multi-Centercase-control study (2004) Prevalence o hepatitisC virus inection in lymphoprolierative diseasesother than B-cell non-Hodgkinrsquos lymphoma and

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Boschi-Pinto C Stuver S Okayama A et al (2000) Aollow-up study o morbidity and mortality associatedwith hepatitis C virus inection and its interaction

with human lymphotropic virus type I in MiyazakiJapan J Infect Dis 181 35ndash41 doi101086315177PMID10608748

Breuhahn K Longerich Schirmacher P (2006)Dysregulation o growth actor signaling in humanhepatocellular carcinoma Oncogene 25 3787ndash3800doi101038sjonc1209556 PMID16799620

Bruno S Crosignani A Maisonneuve P et al (2007)Hepatitis C virus genotype 1b as a major risk actorassociated with hepatocellular carcinoma in patientswith cirrhosis a seventeen-year prospective cohortstudy Hepatology 46 1350ndash1356 doi101002hep21826 PMID17680653

Bruno S Silini E Crosignani A et al (1997) Hepatitis C virus genotypes and risk o hepatocellular carcinoma incirrhosis a prospective study Hepatology 25 754ndash758doi101002hep510250344 PMID9049231

Chang KS Cai Z Zhang C et al (2006) Replication ohepatitis C virus (HCV) RNA in mouse embryonicfibroblasts protein kinase R (PKR)-dependent andPKR-independent mechanisms or controlling HCVRNA replication and mediating intereron activi-ties J Virol 80 7364ndash7374 doi101128JVI00586-06PMID16840317

Chindamo MC Spector N Segadas JA et al (2002)Prevalence o hepatitis C inection in patients withnon-Hodgkinrsquos lymphomas Oncol Rep 9 657ndash659

PMID11956646Cho J Baek W Yang S et al (2001) HCV core protein

modulates Rb pathway through pRb down-regula-tion and E2F-1 up-regulation Biochim Biophys Acta1538 59ndash66 doi101016S0167-4889(00)00137-3PMID11341983

Choo QL Kuo G Weiner AJ et al (1989) Isolation oa cDNA clone derived rom a blood-borne non-Anon-B viral hepatitis genome Science 244 359ndash362doi101126science2523562 PMID2523562

Clarke A amp Kulasegaram R (2006) Hepatitis C transmis-sion ndash where are we now Int J SD AIDS 17 74ndash80 quiz80 doi101258095646206775455685 PMID16464265

Colin C Lanoir D ouzet S et alHEPAIIS Group(2001) Sensitivity and specificity o third-generationhepatitis C virus antibody detection assays an analysiso the literature J Viral Hepat 8 87ndash95 doi101046 j1365-2893200100280x PMID11264728

Cowgill KD Loffredo CA Eissa SA et al (2004) Case-control study o non-Hodgkinrsquos lymphoma and hepa-titis C virus inection in Egypt Int J Epidemiol 331034ndash1039 doi101093ijedyh183 PMID15155696

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Cristoari G Ivanyi-Nagy R Gabus C et al (2004) Tehepatitis C virus Core protein is a potent nucleic acidchaperone that directs dimerization o the viral (+)strand RNA in vitro Nucleic Acids Res 32 2623ndash2631doi101093nargkh579 PMID15141033

Dal Maso L amp Franceschi S (2006) Hepatitis C virus and risk

o lymphoma and other lymphoid neoplasms a meta-analysis o epidemiologic studies Cancer EpidemiolBiomarkers Prev 15 2078ndash2085 doi1011581055-9965EPI-06-0308 PMID17119031

Davila JA Morgan RO Shaib Y et al (2005) Diabetesincreases the risk o hepatocellular carcinoma inthe United States a population based case controlstudy Gut 54 533ndash539 doi101136gut2004052167 PMID15753540

De Rosa G Gobbo ML De Renzo A et al (1997) Highprevalence o hepatitis C virus inection in patientswith B-cell lymphoprolierative disorders in Italy Am J Hematol 55 77ndash82 doi101002(SICI)1096-

8652(199706)552lt77 AID-AJH5gt30CO2- PMID9209002de Sanjoseacute S Benavente Y Vajdic CM et al (2008) Hepatitis

C and non-Hodgkin lymphoma among 4784 casesand 6269 controls rom the International LymphomaEpidemiology Consortium Clin GastroenterolHepatol 6 451ndash458 doi101016jcgh200802011 PMID18387498

de Sanjoseacute S Nieters A Goedert JJ et al (2004) Role ohepatitis C virus inection in malignant lymphoma inSpain Int J Cancer 111 81ndash85 doi101002ijc11727 PMID15185347

De Vita S Zagonel V Russo A et al (1998) Hepatitis C virus non-Hodgkinrsquos lymphomas and hepatocel lular

carcinoma Br J Cancer 77 2032ndash2035 doi101038bjc1998338 PMID9667688

Des Jarlais DC Diaz Perlis et al (2003) Variabilityin the incidence o human immunodeficiency virushepatitis B virus and hepatitis C virus inectionamong young injecting drug users in New York City Am J Epidemiol 157 467ndash471 doi101093ajekw222 PMID12615611

Deutsch M amp Hadziyannis SJ (2008) Old and emergingtherapies in chronic hepatitis C an update J ViralHepat 15 2ndash11 PMID18088238

Dharancy S Malapel M Perlemuter G et al (2005)Impaired expression o the peroxisome prolierator-

activated receptor alpha during hepatitis C virus inec-tion Gastroenterology 128 334ndash342 doi101053jgastro200411016 PMID15685545

Dimitrova M Imbert I Kieny MP Schuster C (2003)Protein-protein interactions between hepatitis C virus nonstructural proteins J Virol 77 5401ndash5414doi101128JVI7795401-54142003 PMID12692242

Domitrovich AM Felmlee DJ Siddiqui A (2005) HepatitisC virus nonstructural proteins inhibit apolipoprotein

B100 secretion J Biol Chem 280 39802ndash39808doi101074jbcM510391200 PMID16203724

Donato F Boffetta P Puoti M (1998) A meta-analysiso epidemiological studies on the combined effect ohepatitis B and C virus inections in causing hepa-tocellular carcinoma Int J Cancer 75 347ndash354

doi101002(SICI)1097-0215(19980130)753lt347AID-IJC4gt30CO2-2 PMID9455792

Donato F Gelatti U agger A et al (2001) Intrahepaticcholangiocarcinoma and hepatitis C and B virus inec-tion alcohol intake and hepatolithiasis a case-controlstudy in Italy Cancer Causes Control 12 959ndash964doi101023A1013747228572 PMID11808716

Donato F agger A Chiesa R et al (1997) Hepatitis Band C virus inection alcohol drinking and hepatocel-lular carcinoma a case-control study in Italy BresciaHCC Study Hepatology 26 579ndash584 doi101002hep510260308 PMID9303486

Donato F agger A Gelatti U et al (2002) Alcohol and

hepatocellular carcinoma the effect o lietime intakeand hepatitis virus inections in men and women Am J Epidemiol 155 323ndash331 doi101093aje1554323 PMID11836196

Duberg AS Nordstroumlm M oumlrner A et al (2005)Non-Hodgkinrsquos lymphoma and other nonhepaticmalignancies in Swedish patients with hepatitis C virus inection Hepatology 41 652ndash659 doi101002hep20608 PMID15723449

Dumoulin FL von dem Bussche A Li J et al (2003)Hepatitis C virus NS2 protein inhibits gene expressionrom different cellular and viral promoters in hepaticand nonhepatic cell lines Virology 305 260ndash266doi101006viro20021701 PMID12573571

Egger D Woumllk B Gosert R et al (2002) Expression ohepatitis C virus proteins induces distinct membranealterations including a candidate viral replica-tion complex J Virol 76 5974ndash5984 doi101128JVI76125974-59842002 PMID12021330

Einav S Elazar M Danieli Glenn JS (2004) A nucle-otide binding moti in hepatitis C virus (HCV)NS4B mediates HCV RNA replication J Virol 7811288ndash11295 doi101128JVI782011288-112952004 PMID15452248

El-Serag HB Hampel H Javadi F (2006) Te associa-tion between diabetes and hepatocellular carcinomaa systematic review o epidemiologic evidence Clin

Gastroenterol Hepatol 4 369ndash380 doi101016jcgh200512007 PMID16527702Engels EA Chatterjee N Cerhan JR et al (2004) Hepatitis

C virus inection and non-Hodgkin lymphomaresults o the NCI-SEER multi-center case-controlstudy Int J Cancer 111 76ndash80 doi101002ijc20021 PMID15185346

Enomoto N Sakuma I Asahina Y et al (1995) Comparisono ull-length sequences o intereron-sensitive andresistant hepatitis C virus 1b Sensitivity to intereron

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is conerred by amino acid substitutions in the NS5Aregion J Clin Invest 96 224ndash230 doi101172JCI118025 PMID7542279

Enomoto N Sakuma I Asahina Y et al (1996) Mutationsin the nonstructural protein 5A gene and response tointereron in patients with chronic hepatitis C virus

1b inection N Engl J Med 334 77ndash81 doi101056NEJM199601113340203 PMID8531962

Erdtmann L Franck N Lerat H et al (2003) Te hepatitisC virus NS2 protein is an inhibitor o CIDE-B-inducedapoptosis J Biol Chem 278 18256ndash18264 doi101074 jbcM209732200 PMID12595532

Evans MJ von Hahn scherne DM et al (2007)Claudin-1 is a hepatitis C virus co-receptor required ora late step in entry Nature 446 801ndash805 doi101038nature05654 PMID17325668

Fattovich G Giustina G Degos F et al (1997) Morbidityand mortality in compensated cirrhosis type Ca retrospective ollow-up study o 384 patients

Gastroenterology 112 463ndash472 doi101053gast1997 v112pm9024300 PMID9024300Ferri C Caracciolo F Zignego AL et al (1994)

Hepatitis C virus inection in patients with non-Hodgkinrsquos lymphoma Br J Haematol 88 392ndash394doi101111j1365-21411994tb05036x PMID7803287

Franceschi S Montella M Polesel J et al (2006a)Hepatitis viruses alcohol and tobacco in the etiologyo hepatocellular carcinoma in Italy Cancer EpidemiolBiomarkers Prev 15 683ndash689 doi1011581055-9965EPI-05-0702 PMID16614109

Franceschi S Polesel J Rickenbach M et al (2006b)Hepatitis C virus and non-Hodgkinrsquos lymphomaFindings rom the Swiss HIV Cohort Study Br J

Cancer 95 1598ndash1602 doi101038sjbjc6603472 PMID17106439

Fukutomi Zhou Y Kawai S et al (2005) Hepatitis C viruscore protein stimulates hepatocyte growth correlationwith upregulation o wnt-1 expression Hepatology 411096ndash1105 doi101002hep20668 PMID15841445

Fusco M Girardi E Piselli P et alCollaborating StudyGroup (2008) Epidemiology o viral hepatitis inec-tions in an area o southern Italy with high inci-dence rates o liver cancer Eur J Cancer 44 847ndash853doi101016jejca200801025 PMID18313290

Gale M Jr Kwieciszewski B Dossett M et al (1999)Antiapoptotic and oncogenic potentials o hepatitis C

virus are linked to intereron resistance by viral repres-sion o the PKR protein kinase J Virol 73 6506ndash6516PMID10400746

Gelatti U Covolo L alamini R et al (2005)N-Acetyltranserase-2 glutathione S-transerase M1and 1 genetic polymorphisms cigarette smokingand hepatocellular carcinoma a case-control studyInt J Cancer 115 301ndash306 doi101002ijc20895 PMID15688397

Giordano P Henderson L Landgren O et al (2007) Risko non-Hodgkin lymphoma and lymphoprolierativeprecursor diseases in US veterans with hepatitis C virus JAMA 297 2010ndash2017 doi101001jama297182010PMID17488966

Gisbert JP Garciacutea-Buey L Pajares JM Moreno-Otero

R (2003) Prevalence o hepatitis C virus inection inB-cell non-Hodgkinrsquos lymphoma systematic reviewand meta-analysis Gastroenterology 125 1723ndash1732doi101053jgastro200309025 PMID14724825

Gisbert JP Garciacutea-Buey L Pajares JM Moreno-Otero R(2005) Systematic review regression o lymphopro-lierative disorders aer treatment or hepatitis Cinection Aliment Pharmacol Ter 21 653ndash662doi101111j1365-2036200502395x PMID15771751

Gong G Waris G anveer R Siddiqui A (2001) Humanhepatitis C virus NS5A protein alters intracellularcalcium levels induces oxidative stress and activates SA-3 and NF-kappa B Proc Natl Acad Sci

USA 98 9599ndash9604 doi101073pnas171311298PMID11481452Gosert R Egger D Lohmann V et al (2003) Identification

o the hepatitis C virus RNA replication complex inHuh-7 cells harboring subgenomic replicons J Virol 77 5487ndash5492 doi101128JVI7795487-54922003PMID12692249

Grakoui A McCourt DW Wychowski C et al (1993)A second hepatitis C virus-encoded proteinase ProcNatl Acad Sci USA 90 10583ndash10587 doi101073pnas902210583 PMID8248148

Griffin S Clarke D McCormick C et al (2005) Signalpeptide cleavage and internal targeting signals directthe hepatitis C virus p7 protein to distinct intracellular

membranes J Virol 79 15525ndash15536 doi101128JVI792415525-155362005 PMID16306623

Guiltinan AM Kaidarova Z Custer B et al (2008)Increased all-cause liver and cardiac mortalityamong hepatitis C virus-seropositive blood donors Am J Epidemiol 167 743ndash750 doi101093ajekwm370PMID18203734

Harakati MS Abualkhair OA Al-Knawy BA (2000)Hepatitis C Virus inection in Saudi Arab patientswith B-cell non-Hodgkinrsquos lymphoma Saudi Med J 21 755ndash758 PMID11423889

Hassan MM Zaghloul AS El-Serag HB et al (2001)Te role o hepatitis C in hepatocellular carcinoma

a case control study among Egyptian patients J ClinGastroenterol 33 123ndash126 doi10109700004836-200108000-00006 PMID11468438

Hatzakis A Katsoulidou A Kaklamani E et al (1996)Hepatitis C virus 1b is the dominant genotype inHCV-related carcinogenesis a case-control studyInt J Cancer 68 51ndash53 doi101002(SICI)1097-0215(19960927)681lt51AID-IJC10gt30CO2-9PMID8895540

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Hayashi J Aoki H Kajino K et al (2000) Hepatitis C virus core protein activates the MAPKERK cascadesynergistically with tumor promoter PA but notwith epidermal growth actor or transorming growthactor alpha Hepatology 32 958ndash961 doi101053 jhep200019343 PMID11050045

He Y Nakao H an SL et al (2002) Subversion o cellsignaling pathways by hepatitis C virus nonstruc-tural 5A protein via interaction with Grb2 and P85phosphatidylinositol 3-kinase J Virol 76 9207ndash9217doi101128JVI76189207-92172002 PMID12186904

Hermine O Leregravere F Bronowicki JP et al (2002)Regression o splenic lymphoma with vi llous lympho-cytes aer treatment o hepatitis C virus inection NEngl J Med 347 89ndash94 doi101056NEJMoa013376 PMID12110736

Hernandez ME Bruguera M Puyuelo et al (1992) Risko needle-stick injuries in the transmission o hepatitisC virus in hospital personnel J Hepatol 16 56ndash58

doi101016S0168-8278(05)80094-7 PMID1484168Hotamisligil GS (2006) Inflammation and meta-bolic disorders Nature 444 860ndash867 doi101038nature05485 PMID17167474

Houghton M amp Abrignani S (2005) Prospects or a vaccineagainst the hepatitis C virus Nature 436 961ndash966doi101038nature04081 PMID16107836

Hsing AW Zhang M Rashid A et al (2008) Hepatitis Band C virus inection and the risk o biliary tract cancera population-based study in China Int J Cancer 1221849ndash1853 doi101002ijc23251 PMID18076042

Hwang LY Kramer JR roisi C et al (2006) Relationshipo cosmetic procedures and drug use to hepatitis Cand hepatitis B virus inections in a low-risk popula-

tion Hepatology 44 341ndash351 doi101002hep21252 PMID16871571

IARC (1988) Alcohol drinking IARC Monogr EvalCarcinog Risks Hum 44 1ndash378 PMID3236394

IARC (1994) Hepatitis viruses IARC Monogr EvalCarcinog Risks Hum 59 1ndash255 PMID7933461

IARC (2004) obacco smoke and involuntary smokingIARC Monogr Eval Carcinog Risks Hum 83 1ndash1438PMID15285078

IARC (2010) Alcohol consumption and ethyl carbamateIARC Monogr Eval Carcinog Risks Hum 96 1ndash1428

Ikeda K Kobayashi M Someya et al (2002) Influenceo hepatitis C virus subtype on hepatocellular carcino-

genesis a multivariate analysis o a retrospective cohorto 593 patients with cirrhosis Intervirology 45 71ndash78doi101159000063230 PMID12145538

Imai Y Ohsawa M anaka H et al (2002) High prevalenceo HCV inection in patients with B-cell non-Hodg-kinrsquos lymphoma comparison with birth cohort- andsex-matched blood donors in a Japanese populationHepatology 35 974ndash976 doi101053jhep200232149 PMID11915049

Imazeki F Yokosuka O Fukai K et al (2003a)Significance o prior hepatitis B virus inection in thedevelopment o hepatocellular carcinoma in patientswith chronic hepatitis C Dig Dis Sci 48 1786ndash1792doi101023A1025459431613 PMID14561002

Imazeki F Yokosuka O Fukai K Saisho H (2003b)

Favorable prognosis o chronic hepatitis C aer inter-eron therapy by long-term cohort study Hepatology 38493ndash502 doi101053jhep200350329 PMID12883494

Iwata H Matsuo K akeuchi K et al (2004) High inci-dences o malignant lymphoma in patients inectedwith hepatitis B or hepatitis C virus Haematologica89 368ndash370 PMID15020283

Jirasko V Montserret R Appel N et al (2008) Structuraland unctional characterization o nonstructuralprotein 2 or its role in hepatitis C virus assembly J BiolChem 283 28546ndash28562 doi101074jbcM803981200 PMID18644781

Joo M Hahn YS Kwon M et al (2005) Hepatitis C virus

core protein suppresses NF-kappaB activation andcyclooxygenase-2 expression by direct interaction withIkappaB kinase beta J Virol 79 7648ndash7657 doi101128JVI79127648-76572005 PMID15919917

Kasahara A Hayashi N Mochizuki K et alOsaka LiverDisease Study Group (1998) Risk actors or hepa-tocellular carcinoma and its incidence aer inter-eron treatment in patients with chronic hepatitis CHepatology 27 1394ndash1402 doi101002hep510270529 PMID9581697

Kawamura Furusaka A Koziel MJ et al (1997)ransgenic expression o hepatitis C virus structuralproteins in the mouse Hepatology 25 1014ndash1021doi101002hep510250437 PMID9096613

Kaya H Polat MF Erdem F Guumlndogdu M (2002)Prevalence o hepatitis C virus and hepatitis G virus in patients with non-Hodgkinrsquos lymphomaClin Lab Haematol 24 107ndash110 doi101046j1365-2257200200427x PMID11985556

Kew MC Yu MC Kedda MA et al (1997) Te relativeroles o hepatitis B and C viruses in the etiology ohepatocellular carcinoma in southern Arican blacksGastroenterology 112 184ndash187 doi101016S0016-5085(97)70233-6 PMID8978357

Koike K (2007) Pathogenesis o HCV-associatedHCC Dual-pass carcinogenesis through activa-tion o oxidative stress and intracellular signaling

Hepatol Res 37 Suppl 2S115ndashS120 doi101111j1872-034X200700173x PMID17877471Kuniyoshi M Nakamuta M Sakai H et al (2001) Prevalence

o hepatitis B or C virus inections in patients withnon-Hodgkinrsquos lymphoma J Gastroenterol Hepatol 16 215ndash219 doi101046j1440-1746200102406x PMID11207904

Kuo G Choo QL Alter HJ et al (1989) An assay orcirculating antibodies to a major etiologic virus o

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Kuper HE zonou A Kaklamani E et al (2000)Hepatitis B and C viruses in the etiology o hepato-cellular carcinoma a study in Greece using third-generation assays Cancer Causes Control 11 171ndash175

doi101023A1008951901148 PMID10710202Kwun HJ amp Jang KL (2003) Dual effects o hepatitis C virus

Core protein on the transcription o cyclin-dependentkinase inhibitor p21 gene J Viral Hepat 10 249ndash255doi101046j1365-2893200300434x PMID12823590

Lai MS Hsieh MS Chiu YH Chen H (2006) ype 2diabetes and hepatocellular carcinoma A cohort studyin high prevalence area o hepatitis virus inectionHepatology 43 1295ndash1302 doi101002hep21208 PMID16729295

Lam AM amp Frick DN (2006) Hepatitis C virus subgenomicreplicon requires an active NS3 RNA helicase J Virol 80 404ndash411 doi101128JVI801404-4112006

PMID16352565Lauer GM amp Walker BD (2001) Hepatitis C virusinection N Engl J Med 345 41ndash52 doi101056NEJM200107053450107 PMID11439948

Lavillette D Bartosch B Nourrisson D et al (2006)Hepatitis C virus glycoproteins mediate lowpH-dependent membrane usion with liposomes J BiolChem 281 3909ndash3917 doi101074jbcM509747200 PMID16356932

Lee Y Lee SS Jung SW et al (2008) Hepatitis B virusinection and intrahepatic cholangiocarcinoma inKorea a case-control study Am J Gastroenterol 1031716ndash1720 doi101111j1572-0241200801796x PMID18557716

Lerat H Honda M Beard MR et al (2002) Steatosisand liver cancer in transgenic mice expressing thestructural and nonstructural proteins o hepatitis C virus Gastroenterology 122 352ndash365 doi101053gast200231001 PMID11832450

Levrero M (2006) Viral hepatitis and liver cancer the caseo hepatitis C Oncogene 25 3834ndash3847 doi101038sjonc1209562 PMID16799625

Liang J amp Heller (2004) Pathogenesis o hepa-titis C-associated hepatocellular carcinomaGastroenterology 127 Suppl 1S62ndashS71 doi101053jgastro200409017 PMID15508105

Lindenbach BD Tiel HJ Rice CM (2007) Flaviviridae

Te Viruses and Teir Replication In Fields Virology 5th edLorenz IC Marcotrigiano J Dentzer G Rice CM (2006)

Structure o the catalytic domain o the hepatitis C virusNS2ndash3 protease Nature 442 831ndash835 doi101038nature04975 PMID16862121

Lu W Lo SY Chen M et al (1999) Activation o p53tumor suppressor by hepatitis C virus core proteinVirology 264 134ndash141 doi101006viro19999979 PMID10544138

Majumder M Ghosh AK Steele R et al (2002) HepatitisC virus NS5A protein impairs NF-mediated hepaticapoptosis but not by an anti-FAS antibody in trans-genic mice Virology 294 94ndash105 doi101006 viro20011309 PMID11886269

Majumder M Steele R Ghosh AK et al (2003) Expression

o hepatitis C virus non-structural 5A protein in theliver o transgenic mice FEBS Lett 555 528ndash532doi101016S0014-5793(03)01337-1 PMID14675768

Manns MP Foster GR Rockstroh JK et al (2007) Teway orward in HCV treatmentndashfinding the right pathNat Rev Drug Discov 6 991ndash1000 doi101038nrd2411PMID18049473

Marcellin P Asselah Boyer N (2002) Fibrosis and diseaseprogression in hepatitis C Hepatology 36 Suppl 1S47ndashS56 doi101002hep1840360707 PMID12407576

Matsuo K Kusano A Sugumar A et al (2004) Effect ohepatitis C virus inection on the risk o non-Hodgkinrsquoslymphoma a meta-analysis o epidemiological studies

Cancer Sci 95 745ndash752 doi101111j1349-70062004tb03256x PMID15471561Matsuzaki K Murata M Yoshida K et al (2007) Chronic

inflammation associated with hepatitis C virus inec-tion perturbs hepatic transorming growth actorbeta signaling promoting cirrhosis and hepatocel-lular carcinoma Hepatology 46 48ndash57 doi101002hep21672 PMID17596875

Mazzaro C Zagonel V Monardini S et al (1996) HepatitisC virus and non-Hodgkinrsquos lymphomas Br J Haematol 94 544ndash550 doi101046j1365-214119966912313xPMID8790157

McGivern DR amp Lemon SM (2009) umor suppres-sors chromosomal instability and hepatitis C

virus-associated liver cancer Annu Rev Pathol 4399ndash415 doi101146annurevpathol4110807092202PMID18928409

McLauchlan J Lemberg MK Hope G Martoglio B(2002) Intramembrane proteolysis promotes tra-ficking o hepatitis C virus core protein to lipid drop-lets EMBO J 21 3980ndash3988 doi101093embojcd414PMID12145199

Mele A Pulsoni A Bianco E et al (2003) Hepatitis C virus and B-cell non-Hodgkin lymphomas an Italianmulticenter case-control study Blood 102 996ndash999doi101182blood-2002-10-3230 PMID12714514

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virus inection in medical personnel aer needle-stick accident Hepatology 16 1109ndash1114 doi101002hep1840160502 PMID1427651

Miyanari Y Atsuzawa K Usuda N et al (2007) Te lipiddroplet is an important organelle or hepatitis C virusproduction Nat Cell Biol 9 1089ndash1097 doi101038ncb1631 PMID17721513

Mizorogi F Hiramoto J Nozato A et al (2000) HepatitisC virus inection in patients with B-cell non-Hodgkinrsquos

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Montella M Crispo A Frigeri F et al (2001b) HCVand tumors correlated with immune system a case-control study in an area o hyperendemicity LeukRes 25 775ndash781 doi101016S0145-2126(01)00027-3 PMID11489471

Moradpour D Englert C Wakita Wands JR (1996)Characterization o cell lines allowing tightly regulatedexpression o hepatitis C virus core protein Virology 222 51ndash63 doi101006viro19960397 PMID8806487

Moradpour D Evans MJ Gosert R et al (2004) Insertiono green fluorescent protein into nonstructural protein5A allows direct visualization o unctional hepatitisC virus replication complexes J Virol 78 7400ndash7409

doi101128JVI78147400-74092004 PMID15220413Moradpour D Penin F Rice CM (2007) Replicationo hepatitis C virus Nat Rev Microbiol 5 453ndash463doi101038nrmicro1645 PMID17487147

Morgensztern D Rosado M Silva O et al (2004)Prevalence o hepatitis C inection in patients withnon-Hodgkinrsquos lymphoma in South Florida and reviewo the literature Leuk Lymphoma 45 2459ndash2464doi10108010428190400007771 PMID15621760

Mori M Hara M Wada I et al (2000) Prospective studyo hepatitis B and C viral inections cigarette smokingalcohol consumption and other actors associated withhepatocellular carcinoma risk in Japan Am J Epidemiol 151 131ndash139 PMID10645815

Moriya K Fujie H Shintani Y et al (1998) Te coreprotein o hepatitis C virus induces hepatocellularcarcinoma in transgenic mice Nat Med 4 1065ndash1067doi1010382053 PMID9734402

Moriya K Fujie H Yotsuyanagi H et al (1997a) Subcellularlocalization o hepatitis C virus structural proteins inthe liver o transgenic mice Jpn J Med Sci Biol 50169ndash177 PMID9556757

Moriya K Nakagawa K Santa et al (2001) Oxidativestress in the absence o inflammation in a mouse modelor hepatitis C virus-associated hepatocarcinogenesisCancer Res 61 4365ndash4370 PMID11389061

Moriya K Yotsuyanagi H Shintani Y et al (1997b)

Hepatitis C virus core protein induces hepatic stea-tosis in transgenic mice J Gen Virol 78 1527ndash1531PMID9225025

Morton LM Engels EA Holord R et al (2004) HepatitisC virus and risk o non-Hodgkin lymphoma a popu-lation-based case-control study among Connecticutwomen Cancer Epidemiol Biomarkers Prev 13425ndash430 PMID15006919

Munakata Nakamura M Liang Y et al (2005) Down-regulation o the retinoblastoma tumor suppressor

by the hepatitis C virus NS5B RNA-dependent RNApolymerase Proc Natl Acad Sci USA 102 18159ndash18164doi101073pnas0505605102 PMID16332962

Murashige N Kami M Iwata H et al (2005) No rela-tionship between hepatitis C inection and risk omyeloid malignancy Haematologica 90 572ndash574

PMID15820965Musto P DellrsquoOlio M Carotenuto M et al (1996) Hepatitis

C virus inection a new bridge between hematolo-gists and gastroenterologists Blood 88 752ndash754PMID8695825

Naoumov NV Chokshi S Metivier E et al (1997) HepatitisC virus inection in the development o hepatocel-lular carcinoma in cirrhosis J Hepatol 27 331ndash336doi101016S0168-8278(97)80179-1 PMID9288608

Negri E Little D Boiocchi M et al (2004) B-cell non-Hodgkinrsquos lymphoma and hepatitis C virus inectiona systematic review Int J Cancer 111 1ndash8 doi101002ijc20205 PMID15185336

Negro F (2006) Mechanisms and significance o liversteatosis in hepatitis C virus inection World JGastroenterol 12 6756ndash6765 PMID17106922

Nelson DR Gonzalez-Peralta RP Qian K et al (1997)ransorming growth actor-beta 1 in chronic hepa-titis C J Viral Hepat 4 29ndash35 doi101046j1365-2893199700124x PMID9031062

Niederau C Lange S Heintges et al (1998) Prognosiso chronic hepatitis C results o a large prospectivecohort study Hepatology 28 1687ndash1695 doi101002hep510280632 PMID9828236

Nielsen SU Bassendine MF Burt AD et al (2006)Association between hepatitis C virus and very-low-density lipoprotein (VLDL)LDL analyzed in iodixanol

density gradients J Virol 80 2418ndash2428 doi101128JVI8052418-24282006 PMID16474148

Nieters A Kallinowski B Brennan P et al (2006)Hepatitis C and risk o lymphoma results o theEuropean multicenter case-control study EPILYMPHGastroenterology 131 1879ndash1886 doi101053jgastro200609019 PMID17087949

Obika M Shinji Fujioka S et al (2008) Hepatitis B virusDNA in liver tissue and risk or hepatocarcinogenesisin patients with hepatitis C virus-related chronic liverdisease A prospective study Intervirology 51 59ndash68doi101159000121363 PMID18349544

Ohsawa M Shingu N Miwa H et al (1999) Risk o

non-Hodgkinrsquos lymphoma in patients with hepa-titis C virus inection Int J Cancer 80 237ndash239doi101002(SICI)1097-0215(19990118)802lt237AID-IJC12gt30CO2-I PMID9935205

Okamoto K Moriishi K Miyamura Matsuura Y (2004)Intramembrane proteolysis and endoplasmic retic-ulum retention o hepatitis C virus core protein J Virol 78 6370ndash6380 doi101128JVI78126370-63802004 PMID15163730

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Hepatitis C virus

Pachiadakis I Pollara G Chain BM Naoumov NV(2005) Is hepatitis C virus inection o dendritic cells amechanism acilitating viral persistence Lancet InfectDis 5 296ndash304 doi101016S1473-3099(05)70114-6 PMID15854885

Pang PS Jankowsky E Planet PJ Pyle AM (2002) Te

hepatitis C viral NS3 protein is a processive DNAhelicase with coactor enhanced RNA unwindingEMBO J 21 1168ndash1176 doi101093emboj2151168 PMID11867545

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Park JS Yang JM Min MK (2000) Hepatitis C virusnonstructural protein NS4B transorms NIH33 cellsin cooperation with the Ha-ras oncogene BiochemBiophys Res Commun 267 581ndash587 doi101006

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Pasquinelli C Shoenberger JM Chung J et al (1997)Hepatitis C virus core and E2 protein expression intransgenic mice Hepatology 25 719ndash727 doi101002hep510250338 PMID9049225

Pavio N Battaglia S Boucreux D et al (2005) HepatitisC virus core variants isolated rom liver tumor but notrom adjacent non-tumor tissue interact with Smad3and inhibit the GF-beta pathway Oncogene 24 6119ndash6132 doi101038sjonc1208749 PMID16007207

Pavio N Romano PR Graczyk M et al (2003) Proteinsynthesis and endoplasmic reticulum stress can bemodulated by the hepatitis C virus envelope proteinE2 through the eukaryotic initiation actor 2alphakinase PERK J Virol 77 3578ndash3585 doi101128JVI7763578-35852003 PMID12610133

Paydas S Kiliccedil B Sahin B Buğdayci R (1999) Prevalence ohepatitis C virus inection in patients with lymphopro-lierative disorders in Southern urkey Br J Cancer 801303ndash1305 doi101038sjbjc6690522 PMID10424729

Pellicano R Mazzaerro V Grigioni WF et al (2004)Helicobacter species sequences in liver samples rompatients with and without hepatocellular carcinoma

World J Gastroenterol 10 598ndash601 PMID14966925Pellicano R Meacutenard A Rizzetto M Meacutegraud F (2008)Helicobacter species and liver diseases association orcausation Lancet Infect Dis 8 254ndash260 doi101016S1473-3099(08)70066-5 PMID18353266

Perlemuter G Sabile A Letteron P et al (2002) HepatitisC virus core protein inhibits microsomal triglyceridetranser protein activity and very low density lipo-protein secretion a model o viral-related steatosis

FASEB J 16 185ndash194 doi101096f01-0396comPMID11818366

Perz JF Armstrong GL Farrington LA et al (2006)Te contributions o hepatitis B virus and hepatitis C virus inections to cirrhosis and primary liver cancerworldwide J Hepatol 45 529ndash538 doi101016j

jhep200605013 PMID16879891Ploss A Evans MJ Gaysinskaya VA et al (2009) Human

occludin is a hepatitis C virus entry actor requiredor inection o mouse cells Nature 457 882ndash886doi101038nature07684 PMID19182773

Polyak SJ Khabar KS Paschal DM et al (2001) Hepatitis C virus nonstructural 5A protein induces interleukin-8leading to partial inhibition o the intereron-inducedantiviral response J Virol 75 6095ndash6106 doi101128JVI75136095-61062001 PMID11390611

Ponzetto A Pellicano R Leone N et al (2000) Helicobacterinection and cirrhosis in hepatitis C virus carriageis it an innocent bystander or a troublemaker Med

Hypotheses 54 275ndash277 doi101054mehy19990987PMID10790764Poynard Yuen MF Ratziu V Lai CL (2003) Viral hepa-

titis C Lancet 362 2095ndash2100 doi101016S0140-6736(03)15109-4 PMID14697814

Rabkin CS ess BH Christianson RE et al (2002)Prospective study o hepatitis C viral inection as a riskactor or subsequent B-cell neoplasia Blood 99 4240ndash4242 doi101182blood-2002-01-0226 PMID12010836

Ray RB Lagging LM Meyer K Ray R (1996) Hepatitis C virus core protein cooperates with ras and transormsprimary rat embryo fibroblasts to tumorigenic pheno-type J Virol 70 4438ndash4443 PMID8676467

Ray RB Steele R Basu A et al (2002) Distinct unctional

role o Hepatitis C virus core protein on NF-kappaBregulation is linked to genomic variation VirusRes 87 21ndash29 doi101016S0168-1702(02)00046-1PMID12135786

Ray RB Steele R Meyer K Ray R (1997) ranscriptionalrepression o p53 promoter by hepatitis C virus coreprotein J Biol Chem 272 10983ndash10986 doi101074 jbc2721710983 PMID9110985

Raza SA Clifford GM Franceschi S (2007) Worldwide variation in the relative importance o hepatitis Band hepatitis C viruses in hepatocellular carcinomaa systematic review Br J Cancer 96 1127ndash1134doi101038sjbjc6603649 PMID17406349

Rocha M Avenaud P Meacutenard A et al (2005) Associationo Helicobacter species with hepatitis C cirrhosis withor without hepatocellular carcinoma Gut 54 396ndash401doi101136gut2004042168 PMID15710989

Roque-Aonso AM Ducoulombier D Di Liberto G et al(2005) Compartmentalization o hepatitis C virusgenotypes between plasma and peripheral bloodmononuclear cells J Virol 79 6349ndash6357 doi101128JVI79106349-63572005 PMID15858018

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Sakai A Claire MS Faulk K et al (2003) Te p7 polypep-tide o hepatitis C virus is critical or inectivity andcontains unctionally important genotype-specificsequences Proc Natl Acad Sci USA 100 11646ndash11651doi101073pnas1834545100 PMID14504405

Sakamuro D Furukawa akegami (1995) Hepatitis C

virus nonstructural protein NS3 transorms NIH 33cells J Virol 69 3893ndash3896 PMID7745741

Schoumlllkop C Smedby KE Hjalgrim H et al (2008)Hepatitis C inection and risk o malignant lymphomaInt J Cancer 122 1885ndash1890 doi101002ijc23416 PMID18271005

Schwer B Ren S Pietschmann et al (2004) argetingo hepatitis C virus core protein to mitochondriathrough a novel C-terminal localization moti J Virol 78 7958ndash7968 doi101128JVI78157958-79682004 PMID15254168

Sell S amp Leffert HL (2008) Liver cancer stem cells J ClinOncol 26 2800ndash2805 doi101200JCO2007155945

PMID18539957Seraty L Aumaicirctre H Chazouillegraveres O et al (1998)Determinants o outcome o compensated hepatitisC virus-related cirrhosis Hepatology 27 1435ndash1440doi101002hep510270535 PMID9581703

Segraveve P Renaudier P Sasco AJ et al (2004) Hepatitis C v irusinection and B-cell non-Hodgkinrsquos lymphoma a cross-sectional study in Lyon France Eur J GastroenterolHepatol 16 1361ndash1365 PMID15618846

Shaib YH El-Serag HB Nooka AK et al (2007) Riskactors or intrahepatic and extrahepatic cholangio-carcinoma a hospital-based case-control study Am J Gastroenterol 102 1016ndash1021 doi101111j1572-0241200701104x PMID17324130

Sharp GB Mizuno Cologne JB et al (2003)Hepatocellular carcinoma among atomic bomb survi- vors significant interaction o radiation with hepa-titis C virus inections Int J Cancer 103 531ndash537doi101002ijc10862 PMID12478671

Shi J Zhu L Liu S Xie WF (2005) A meta-analysis ocase-control studies on the combined effect o hepa-titis B and C virus inections in causing hepatocel-lular carcinoma in China Br J Cancer 92 607ndash612PMID15685242

Shimakami Hijikata M Luo H et al (2004) Effect ointeraction between hepatitis C virus NS5A and NS5Bon hepatitis C virus RNA replication with the hepatitis

C virus replicon J Virol 78 2738ndash2748 doi101128JVI7862738-27482004 PMID14990694Shimizu YK Igarashi H Kiyohara et al (1998) Inection

o a chimpanzee with hepatitis C virus grown in cellculture J Gen Virol 79 1383ndash1386 PMID9634078

Shimoda R Nagashima M Sakamoto M et al (1994)Increased ormation o oxidative DNA damage8-hydroxydeoxyguanosine in human livers withchronic hepatitis Cancer Res 54 3171ndash3172PMID8205535

Shimoike Mimori S ani H et al (1999) Interaction ohepatitis C virus core protein with viral sense RNA andsuppression o its translation J Virol 73 9718ndash9725PMID10559281

Shin HR Lee CU Park HJ et al (1996) Hepatitis B and C virus Clonorchis sinensis or the risk o liver cancer a

case-control study in Pusan Korea Int J Epidemiol 25933ndash940 doi101093ije255933 PMID8921477

Shirota Y Luo H Qin W et al (2002) Hepatitis C virus(HCV) NS5A binds RNA-dependent RNA polymerase(RdRP) NS5B and modulates RNA-dependent RNApolymerase activity J Biol Chem 277 11149ndash11155doi101074jbcM111392200 PMID11801599

Silini E Bottelli R Asti M et al (1996) Hepatitis C virus genotypes and risk o hepatocellular carcinomain cirrhosis a case-control study Gastroenterology 111 199ndash205 doi101053gast1996v111pm8698200 PMID8698200

Silvestri F Pipan C Barillari G et al (1996) Prevalence

o hepatitis C virus inection in patients withlymphoprolierative disorders Blood 87 4296ndash4301PMID8639788

Simmonds P Bukh J Combet C et al (2005) Consensusproposals or a unified system o nomenclature ohepatitis C virus genotypes Hepatology 42 962ndash973doi101002hep20819 PMID16149085

Sonmez M Bektas O Yilmaz M et al (2007) Te rela-tion o lymphoma and hepatitis B virushepatitis C virus inections in the region o East Black Sea urkeyumori 93 536ndash539 PMID18338485

Spinelli JJ Lai AS Krajden M et al (2008) Hepatitis C virus and risk o non-Hodgkin lymphoma in BritishColumbia Canada Int J Cancer 122 630ndash633

doi101002ijc23105 PMID17935132Steinmann E Penin F Kallis S et al (2007) Hepatitis C

virus p7 protein is crucial or assembly and release oinectious virions PLoS Pathog 3 e103 doi101371 journalppat0030103 PMID17658949

Street A Macdonald A Crowder K Harris M (2004)Te Hepatitis C virus NS5A protein activates a phos-phoinositide 3-kinase-dependent survival signalingcascade J Biol Chem 279 12232ndash12241 doi101074 jbcM312245200 PMID14709551

Street A Macdonald A McCormick C Harris M (2005)Hepatitis C virus NS5A-mediated activation o phos-phoinositide 3-kinase results in stabilization o cellular

beta-catenin and stimulation o beta-catenin-respon-sive transcription J Virol 79 5006ndash5016 doi101128JVI7985006-50162005 PMID15795286

Suarez F Lortholary O Hermine O Lecuit M (2006)Inection-associated lymphomas derived rom marginalzone B cel ls a model o antigen-driven lymphoprolier-ation Blood 107 3034ndash3044 doi101182blood-2005-09-3679 PMID16397126

Sumida Y Nakashima Yoh et al (2000) Serumthioredoxin levels as an indicator o oxidative stress in

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Sun CA Wu DM Lin CC et al (2003) Incidence andcoactors o hepatitis C virus-related hepatocellularcarcinoma a prospective study o 12008 men in

aiwan Am J Epidemiol 157 674ndash682 doi101093ajekwg041 PMID12697571

Sung VM Shimodaira S Doughty AL et al (2003)Establishment o B-cell lymphoma cell lines persis-tently inected with hepatitis C virus in vivo and in vitro the apoptotic effects o virus inection J Virol 77 2134ndash2146 doi101128JVI7732134-21462003 PMID12525648

Suruki RY Mueller N Hayashi K et al (2006) Hostimmune status and incidence o hepatocellular carci-noma among subjects inected with hepatitis C virusa nested case-control study in Japan Cancer EpidemiolBiomarkers Prev 15 2521ndash2525 doi1011581055-9965

EPI-06-0485 PMID17164379agger A Donato F Ribero ML et al (1999) Case-controlstudy on hepatitis C virus (HCV) as a risk actor orhepatocellular carcinoma the role o HCV geno-types and the synergism with hepatitis B virus andalcohol Brescia HCC Study Int J Cancer 81 695ndash699doi101002(SICI)1097-0215(19990531)815lt695AID-IJC4gt30CO2-W PMID10328218

alamini R Montella M Crovatto M et al (2004)Non-Hodgkinrsquos lymphoma and hepatitis C virusa case-control study rom northern and southernItaly Int J Cancer 110 380ndash385 doi101002ijc20137 PMID15095303

anaka H sukuma H Yamano H et al (1998a) Hepatitis

C virus 1b(II) inection and development o chronichepatitis liver cirrhosis and hepatocellular carcinomaa case-control study in Japan J Epidemiol 8 244ndash249PMID9816816

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anaka K Sakai H Hashizume M Hirohata (1998b)A long-term ollow-up study on risk actors orhepatocellular carcinoma among Japanese patientswith liver cirrhosis Jpn J Cancer Res 89 1241ndash1250

PMID10081484anaka N Moriya K Kiyosawa K et al (2008) PPARalphaactivation is essential or HCV core protein-inducedhepatic steatosis and hepatocellular carcinoma in mice J Clin Invest 118 683ndash694 PMID18188449

anaka Kato N Cho MJ Shimotohno K (1995) A novelsequence ound at the 3prime terminus o hepatitis C virusgenome Biochem Biophys Res Commun 215 744ndash749doi101006bbrc19952526 PMID7488017

ardi KD Mori K Siddiqui A (2002) Hepatitis C virussubgenomic replicons induce endoplasmic reticulumstress activating an intracellular signaling pathway J Virol 76 7453ndash7459 doi101128JVI76157453-74592002 PMID12097557

ardi KD Waris G Siddiqui A (2005) Hepatitis C v irus

ER stress and oxidative stress rends Microbiol 13159ndash163 doi101016jtim200502004 PMID15817385

aylor DR Shi S Romano PR et al (1999) Inhibitiono the intereron-inducible protein kinase PKR byHCV E2 protein Science 285 107ndash110 doi101126science2855424107 PMID10390359

Torgeirsson SS amp Grisham JW (2002) Molecular patho-genesis o human hepatocellular carcinoma Nat Genet 31 339ndash346 doi101038ng0802-339 PMID12149612

ong MJ el-Farra NS Reikes AR Co RL (1995)Clinical outcomes aer transusion-associated hepa-titis C N Engl J Med 332 1463ndash1466 doi101056NEJM199506013322202 PMID7739682

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sukuma H Hiyama anaka S et al (1993) Risk actorsor hepatocellular carcinoma among patients withchronic liver disease N Engl J Med 328 1797ndash1801doi101056NEJM199306243282501 PMID7684822

Ulcickas Yood M Quesenberry CP Jr Guo D et al

(2007) Incidence o non-Hodgkinrsquos lymphoma amongindividuals with chronic hepatitis B virus inec-tion Hepatology 46 107ndash112 doi101002hep21642PMID17526021

Vajdic CM Grulich AE Kaldor JM et al (2006) Specificinections inection-related behavior and risk onon-Hodgkin lymphoma in adults Cancer EpidemiolBiomarkers Prev 15 1102ndash1108 doi1011581055-9965EPI-06-0078 PMID16775166

Vallisa D Bertegrave R Rocca A et al (1999) Associationbetween hepatitis C virus and non-Hodgkinrsquoslymphoma and effects o viral inection on histologicsubtype and clinical course Am J Med 106 556ndash560

doi101016S0002-9343(99)00069-8 PMID10335728Wakita aya C Katsume A et al (1998) Efficient condi-tional transgene expression in hepatitis C virus cDNAtransgenic mice mediated by the CreloxP system JBiol Chem 273 9001ndash9006 doi101074jbc273159001PMID9535887

Wang C Gale M Jr Keller BC et al (2005) Identificationo FBL2 as a geranylgeranylated cellular proteinrequired or hepatitis C virus RNA replication Mol

167

7232019 mono100B-8



Cell 18 425ndash434 doi101016jmolcel200504004 PMID15893726

Wang LY You SL Lu SN et al (2003) Risk o hepato-cellular carcinoma and habits o alcohol drinkingbetel quid chewing and cigarette smoking a cohorto 2416 HBsAg-seropositive and 9421 HBsAg-

seronegative male residents in aiwan Cancer CausesControl 14 241ndash250 doi101023A1023636619477 PMID12814203

Waris G Felmlee DJ Negro F Siddiqui A (2007) HepatitisC virus induces proteolytic cleavage o sterol regulatoryelement binding proteins and stimulates their phos-phorylation via oxidative stress J Virol 81 8122ndash8130doi101128JVI00125-07 PMID17507484

Watashi K Ishii N Hijikata M et al (2005) CyclophilinB is a unctional regulator o hepatitis C virus RNApolymerase Mol Cell 19 111ndash122 doi101016jmolcel200505014 PMID15989969

Watashi K amp Shimotohno K (2007) Chemical genetics

approach to hepatitis C virus replication cyclophilin asa target or anti-hepatitis C virus strategyRev Med Virol 17 245ndash252 doi101002rmv534 PMID17299803

Waters L Stebbing J Mandalia S et al (2005) Hepatitis Cinection is not associated with systemic HIV-associatednon-Hodgkinrsquos lymphoma a cohort study Int J Cancer 116 161ndash163 doi101002ijc20988 PMID15756687

Welzel M Graubard BI El-Serag HB et al (2007) Riskactors or intrahepatic and extrahepatic cholangiocar-cinoma in the United States a population-based case-control study Clin Gastroenterol Hepatol 5 1221ndash1228doi101016jcgh200705020 PMID17689296

Wetterau JR Lin MC Jamil H (1997) Microsomal triglyc-eride transer protein Biochim Biophys Acta 1345

136ndash150 PMID9106493Xu Z Fan X Xu Y Di Bisceglie AM (2008) Comparative

analysis o nearly ull-length hepatitis C virus quasispe-cies rom patients experiencing viral breakthroughduring antiviral therapy clustered mutations in threeunctional genes E2 NS2 and NS5a J Virol 82 9417ndash9424 doi101128JVI00896-08 PMID18667493

Yamamoto S Kubo S Hai S et al (2004) HepatitisC virus inection as a likely etiology o intra-hepatic cholangiocarcinoma Cancer Sci 95592ndash595 doi101111j1349-70062004tb02492x PMID15245596

Yasui K Wakita sukiyama-Kohara K et al (1998) Te

native orm and maturation process o hepatitis C viruscore protein J Virol 72 6048ndash6055 PMID9621068Yenice N Guumllluumlk F Arican N uumlrkmen S (2003) HCV

prevalence in Hodgkin and non-Hodgkin lymphomacases urk J Gastroenterol 14 173ndash176 PMID14655060

Yuan JM Govindarajan S Arakawa K Yu MC (2004)Synergism o alcohol diabetes and viral hepatitis onthe risk o hepatocellular carcinoma in blacks and

Yuan JM Ross RK Stanczyk FZ et al (1995) A cohortstudy o serum testosterone and hepatocellular carci-noma in Shanghai China Int J Cancer 63 491ndash493doi101002ijc2910630405 PMID7591255

Zhang M Sun XD Mark SD et al (2005) Hepatitis C virus inection Linxian China Emerg Infect Dis 11

17ndash21 PMID15705317Zhu Q Guo J Seeger C (2003) Replication o hepatitis C

virus subgenomes in nonhepatic epithelial and mousehepatoma cells J Virol 77 9204ndash9210 doi101128JVI77179204-92102003 PMID12915536

Zoulim F (2006) New nucleic acid diagnostic testsin viral hepatitis Semin Liver Dis 26 309ndash317doi101055s-2006-951602 PMID17051445

Zucca E Roggero E Maggi-Solcagrave N et al (2000)Prevalence o Helicobacter pylori and hepatitis C virusinections among non-Hodgkinrsquos lymphoma patientsin Southern Switzerland Haematologica 85 147ndash153PMID10681721

Zuckerman E Zuckerman Levine AM et al (1997)Hepatitis C virus inection in patients with B-cell non-Hodgkin lymphoma Ann Intern Med 127 423ndash428PMID9312998

7232019 mono100B-8



orms into a complex secondary structure isneeded or efficient RNA replication and drivescap-independent translation o a single largeopen reading rame (ORF) that encodes approxi-mately 3000 residues (Moradpour et al 2007)Te HCV 3prime NCR consists o a short variabledomain o about 40nt and a polyuridinepolypy-rimidine tract ollowed by a highly conserveddomain o 98nt that is essential or RNA replica-tion (anaka et al 1995) Te N -terminal regiono the polyprotein encodes the structural proteinsincluding the nucleocapsid protein (core) andtwo envelope glycoproteins (E1 and E2) thatorm the viral particle ollowed by several non-structural proteins designated as NS2 to NS5B

(Fig 11) Te C -terminal regions o the coreand envelope proteins contain signal sequencesand are cleaved in the endoplasmic reticulum byhost signal peptidase and signal peptide pepti-dase (Yasui et al 1998 McLauchlan et al 2002Okamoto et al 2004) Alternative cleavage sitesat the C -terminal o E2 yield the viroporin p7Te NS2NS3 junction is cleaved in cis by metal-loproteinase activity Te remaining cleavagesare carried out by the NS3 serine protease whichrequires NS4A as a coactor Besides partici-

pating in polyprotein processing NS2 playsimportant roles in viral assembly (Moradpour et al 2007 Jirasko et al 2008) Te non-struc-tural genes NS3 NS4A NS4B NS5A and NS5B have diverse unctions (see Section 4) and areall required or RNA replication (Lindenbach et al 2007 Moradpour et al 2007) NS5B the

viral replicase lacks prooreading activity Tislack o prooreading in the context o a veryhigh viral production rate which has been esti-

mated to be as much as 1012

virions per day ininected patients is thought to be responsible orthe high genetic variability o HCV (Moradpour et al 2007) Tus HCV has been classifiedinto six genotypes and several subtypes basedon sequence similarities In addition the HCVgenome is prone to acquiring mutations that

lead to the presence o quasi-species in inectedpatients (Xu et al 2008)

114 Host range

HCV is hepatotropic and only man andhigher primates such as chimpanzees have beenuntil recently receptive to HCV inection anddisease Later it was shown that the marmosetas well as tupaias which are members o thetree shrew genus are also susceptible to HCVinection (Shimizu et al 1998 Sung et al 2003Pachiadakis et al 2005)

115 Tissue target

While HCV RNA has been unequivocallydetected in the hepatocytes o liver biopsies ochronically inected patients and chimpan-zees the HCV genome has also been suggestedto replicate in cells o lymphoid origin anddendritic cells (Shimizu et al 1998 Sung et al 2003 Pachiadakis et al 2005) but this observa-tion remains to be substantiated Whether thetropism o HCV is limited to hepatocytes at thelevel o cell entry andor replication via the asso-

ciation o HCV with lipoproteins andor by otheractors remains unclear Expression patterns oall cell entry actors isolated to date are eitherubiquitous or not unique to hepatocytes Tisincludes the lipoprotein receptors scavengerreceptor B1 (SR-B1) and the low-density lipopro-tein receptor (LDLr) which may mediate indirectuptake o HCV via HCV-associated lipoproteins(Moradpour et al 2007) Te replication o HCVseems mostly restricted to hepatocytes and eventhough HCV replicons have been shown to

ampliy in cell lines o non-hepatic origin thelevels o replication reported are significantlylower than those observed in cell lines o hepaticorigin (Zhu et al 2003 Ali et al 2004 Chang et al 2006)

136

7232019 mono100B-8


Hepatitis C virus







137



7232019 mono100B-8


















138

7232019 mono100B-8


Hepatitis C virus

139

F i g

1 2



g i o n


7232019 mono100B-8


















140

7232019 mono100B-8


Hepatitis C virus

2 Cancer in Humans








211 Cohort studies








141

7232019 mono100B-8







213 Meta-analyses




214 HCV genotype


142

7232019 mono100B-8


Hepatitis C virus










(b) Smoking





143

7232019 mono100B-8





















(a) Cohort studies






144

7232019 mono100B-8


Hepatitis C virus






(a) Cohort studies







145

7232019 mono100B-8















146

7232019 mono100B-8


Hepatitis C virus












147

7232019 mono100B-8




(c) Meta-analyses











148

7232019 mono100B-8


Hepatitis C virus



223 Other cancers

(a) Leukaemias















149

7232019 mono100B-8










See able 41


(a) Core protein







(a) p7



150

7232019 mono100B-8


Hepatitis C virus

(b) NS2


Jirasko et al 2008)

(c) NS3



(d) NS4A



151







Apoptosis


Cell entry









Oxydative stress






7232019 mono100B-8



(e) NS4B



(f) NS5A


(g) NS5B





See able 41






152

7232019 mono100B-8


Hepatitis C virus



(a) Core protein















153

7232019 mono100B-8




(b) NS2


(c) NS3-4A



(d) NS5A












154

7232019 mono100B-8


Hepatitis C virus

















155

7232019 mono100B-8















156

7232019 mono100B-8


Hepatitis C virus

















157

7232019 mono100B-8









47 Synthesis





5 Evaluation




References




158

7232019 mono100B-8


Hepatitis C virus
































159

7232019 mono100B-8


































160

7232019 mono100B-8


Hepatitis C virus
































161

7232019 mono100B-8


































162

7232019 mono100B-8


Hepatitis C virus


































163

7232019 mono100B-8


































164

7232019 mono100B-8


Hepatitis C virus






























165

7232019 mono100B-8



































166

7232019 mono100B-8


Hepatitis C virus





























167

7232019 mono100B-8



























7232019 mono100B-8


Hepatitis C virus







137



7232019 mono100B-8


















138

7232019 mono100B-8


Hepatitis C virus

139

F i g

1 2



g i o n


7232019 mono100B-8


















140

7232019 mono100B-8


Hepatitis C virus

2 Cancer in Humans








211 Cohort studies








141

7232019 mono100B-8







213 Meta-analyses




214 HCV genotype


142

7232019 mono100B-8


Hepatitis C virus










(b) Smoking





143

7232019 mono100B-8





















(a) Cohort studies






144

7232019 mono100B-8


Hepatitis C virus






(a) Cohort studies







145

7232019 mono100B-8















146

7232019 mono100B-8


Hepatitis C virus












147

7232019 mono100B-8




(c) Meta-analyses











148

7232019 mono100B-8


Hepatitis C virus



223 Other cancers

(a) Leukaemias















149

7232019 mono100B-8










See able 41


(a) Core protein







(a) p7



150

7232019 mono100B-8


Hepatitis C virus

(b) NS2


Jirasko et al 2008)

(c) NS3



(d) NS4A



151







Apoptosis


Cell entry









Oxydative stress






7232019 mono100B-8



(e) NS4B



(f) NS5A


(g) NS5B





See able 41






152

7232019 mono100B-8


Hepatitis C virus



(a) Core protein















153

7232019 mono100B-8




(b) NS2


(c) NS3-4A



(d) NS5A












154

7232019 mono100B-8


Hepatitis C virus

















155

7232019 mono100B-8















156

7232019 mono100B-8


Hepatitis C virus

















157

7232019 mono100B-8









47 Synthesis





5 Evaluation




References




158

7232019 mono100B-8


Hepatitis C virus
































159

7232019 mono100B-8


































160

7232019 mono100B-8


Hepatitis C virus
































161

7232019 mono100B-8


































162

7232019 mono100B-8


Hepatitis C virus


































163

7232019 mono100B-8


































164

7232019 mono100B-8


Hepatitis C virus






























165

7232019 mono100B-8



































166

7232019 mono100B-8


Hepatitis C virus





























167

7232019 mono100B-8



























7232019 mono100B-8


















138

7232019 mono100B-8


Hepatitis C virus

139

F i g

1 2



g i o n


7232019 mono100B-8


















140

7232019 mono100B-8


Hepatitis C virus

2 Cancer in Humans








211 Cohort studies








141

7232019 mono100B-8







213 Meta-analyses




214 HCV genotype


142

7232019 mono100B-8


Hepatitis C virus










(b) Smoking





143

7232019 mono100B-8





















(a) Cohort studies






144

7232019 mono100B-8


Hepatitis C virus






(a) Cohort studies







145

7232019 mono100B-8















146

7232019 mono100B-8


Hepatitis C virus












147

7232019 mono100B-8




(c) Meta-analyses











148

7232019 mono100B-8


Hepatitis C virus



223 Other cancers

(a) Leukaemias















149

7232019 mono100B-8










See able 41


(a) Core protein







(a) p7



150

7232019 mono100B-8


Hepatitis C virus

(b) NS2


Jirasko et al 2008)

(c) NS3



(d) NS4A



151







Apoptosis


Cell entry









Oxydative stress






7232019 mono100B-8



(e) NS4B



(f) NS5A


(g) NS5B





See able 41






152

7232019 mono100B-8


Hepatitis C virus



(a) Core protein















153

7232019 mono100B-8




(b) NS2


(c) NS3-4A



(d) NS5A












154

7232019 mono100B-8


Hepatitis C virus

















155

7232019 mono100B-8















156

7232019 mono100B-8


Hepatitis C virus

















157

7232019 mono100B-8









47 Synthesis





5 Evaluation




References




158

7232019 mono100B-8


Hepatitis C virus
































159

7232019 mono100B-8


































160

7232019 mono100B-8


Hepatitis C virus
































161

7232019 mono100B-8


































162

7232019 mono100B-8


Hepatitis C virus


































163

7232019 mono100B-8


































164

7232019 mono100B-8


Hepatitis C virus






























165

7232019 mono100B-8



































166

7232019 mono100B-8


Hepatitis C virus





























167

7232019 mono100B-8



























7232019 mono100B-8


Hepatitis C virus

139

F i g

1 2



g i o n


7232019 mono100B-8


















140

7232019 mono100B-8


Hepatitis C virus

2 Cancer in Humans








211 Cohort studies








141

7232019 mono100B-8







213 Meta-analyses




214 HCV genotype


142

7232019 mono100B-8


Hepatitis C virus










(b) Smoking





143

7232019 mono100B-8





















(a) Cohort studies






144

7232019 mono100B-8


Hepatitis C virus






(a) Cohort studies







145

7232019 mono100B-8















146

7232019 mono100B-8


Hepatitis C virus












147

7232019 mono100B-8




(c) Meta-analyses











148

7232019 mono100B-8


Hepatitis C virus



223 Other cancers

(a) Leukaemias















149

7232019 mono100B-8










See able 41


(a) Core protein







(a) p7



150

7232019 mono100B-8


Hepatitis C virus

(b) NS2


Jirasko et al 2008)

(c) NS3



(d) NS4A



151







Apoptosis


Cell entry









Oxydative stress






7232019 mono100B-8



(e) NS4B



(f) NS5A


(g) NS5B





See able 41






152

7232019 mono100B-8


Hepatitis C virus



(a) Core protein















153

7232019 mono100B-8




(b) NS2


(c) NS3-4A



(d) NS5A












154

7232019 mono100B-8


Hepatitis C virus

















155

7232019 mono100B-8















156

7232019 mono100B-8


Hepatitis C virus

















157

7232019 mono100B-8









47 Synthesis





5 Evaluation




References




158

7232019 mono100B-8


Hepatitis C virus
































159

7232019 mono100B-8


































160

7232019 mono100B-8


Hepatitis C virus
































161

7232019 mono100B-8


































162

7232019 mono100B-8


Hepatitis C virus


































163

7232019 mono100B-8


































164

7232019 mono100B-8


Hepatitis C virus






























165

7232019 mono100B-8



































166

7232019 mono100B-8


Hepatitis C virus





























167

7232019 mono100B-8



























7232019 mono100B-8


















140

7232019 mono100B-8


Hepatitis C virus

2 Cancer in Humans








211 Cohort studies








141

7232019 mono100B-8







213 Meta-analyses




214 HCV genotype


142

7232019 mono100B-8


Hepatitis C virus










(b) Smoking





143

7232019 mono100B-8





















(a) Cohort studies






144

7232019 mono100B-8


Hepatitis C virus






(a) Cohort studies







145

7232019 mono100B-8















146

7232019 mono100B-8


Hepatitis C virus












147

7232019 mono100B-8




(c) Meta-analyses











148

7232019 mono100B-8


Hepatitis C virus



223 Other cancers

(a) Leukaemias















149

7232019 mono100B-8










See able 41


(a) Core protein







(a) p7



150

7232019 mono100B-8


Hepatitis C virus

(b) NS2


Jirasko et al 2008)

(c) NS3



(d) NS4A



151







Apoptosis


Cell entry









Oxydative stress






7232019 mono100B-8



(e) NS4B



(f) NS5A


(g) NS5B





See able 41






152

7232019 mono100B-8


Hepatitis C virus



(a) Core protein















153

7232019 mono100B-8




(b) NS2


(c) NS3-4A



(d) NS5A












154

7232019 mono100B-8


Hepatitis C virus

















155

7232019 mono100B-8















156

7232019 mono100B-8


Hepatitis C virus

















157

7232019 mono100B-8









47 Synthesis





5 Evaluation




References




158

7232019 mono100B-8


Hepatitis C virus
































159

7232019 mono100B-8


































160

7232019 mono100B-8


Hepatitis C virus
































161

7232019 mono100B-8


































162

7232019 mono100B-8


Hepatitis C virus


































163

7232019 mono100B-8


































164

7232019 mono100B-8


Hepatitis C virus






























165

7232019 mono100B-8



































166

7232019 mono100B-8


Hepatitis C virus





























167

7232019 mono100B-8



























7232019 mono100B-8


Hepatitis C virus

2 Cancer in Humans








211 Cohort studies








141

7232019 mono100B-8







213 Meta-analyses




214 HCV genotype


142

7232019 mono100B-8


Hepatitis C virus










(b) Smoking





143

7232019 mono100B-8





















(a) Cohort studies






144

7232019 mono100B-8


Hepatitis C virus






(a) Cohort studies







145

7232019 mono100B-8















146

7232019 mono100B-8


Hepatitis C virus












147

7232019 mono100B-8




(c) Meta-analyses











148

7232019 mono100B-8


Hepatitis C virus



223 Other cancers

(a) Leukaemias















149

7232019 mono100B-8










See able 41


(a) Core protein







(a) p7



150

7232019 mono100B-8


Hepatitis C virus

(b) NS2


Jirasko et al 2008)

(c) NS3



(d) NS4A



151







Apoptosis


Cell entry









Oxydative stress






7232019 mono100B-8



(e) NS4B



(f) NS5A


(g) NS5B





See able 41






152

7232019 mono100B-8


Hepatitis C virus



(a) Core protein















153

7232019 mono100B-8




(b) NS2


(c) NS3-4A



(d) NS5A












154

7232019 mono100B-8


Hepatitis C virus

















155

7232019 mono100B-8















156

7232019 mono100B-8


Hepatitis C virus

















157

7232019 mono100B-8









47 Synthesis





5 Evaluation




References




158

7232019 mono100B-8


Hepatitis C virus
































159

7232019 mono100B-8


































160

7232019 mono100B-8


Hepatitis C virus
































161

7232019 mono100B-8


































162

7232019 mono100B-8


Hepatitis C virus


































163

7232019 mono100B-8


































164

7232019 mono100B-8


Hepatitis C virus






























165

7232019 mono100B-8



































166

7232019 mono100B-8


Hepatitis C virus





























167

7232019 mono100B-8



























7232019 mono100B-8







213 Meta-analyses




214 HCV genotype


142

7232019 mono100B-8


Hepatitis C virus










(b) Smoking





143

7232019 mono100B-8





















(a) Cohort studies






144

7232019 mono100B-8


Hepatitis C virus






(a) Cohort studies







145

7232019 mono100B-8















146

7232019 mono100B-8


Hepatitis C virus












147

7232019 mono100B-8




(c) Meta-analyses











148

7232019 mono100B-8


Hepatitis C virus



223 Other cancers

(a) Leukaemias















149

7232019 mono100B-8










See able 41


(a) Core protein







(a) p7



150

7232019 mono100B-8


Hepatitis C virus

(b) NS2


Jirasko et al 2008)

(c) NS3



(d) NS4A



151







Apoptosis


Cell entry









Oxydative stress






7232019 mono100B-8



(e) NS4B



(f) NS5A


(g) NS5B





See able 41






152

7232019 mono100B-8


Hepatitis C virus



(a) Core protein















153

7232019 mono100B-8




(b) NS2


(c) NS3-4A



(d) NS5A












154

7232019 mono100B-8


Hepatitis C virus

















155

7232019 mono100B-8















156

7232019 mono100B-8


Hepatitis C virus

















157

7232019 mono100B-8









47 Synthesis





5 Evaluation




References




158

7232019 mono100B-8


Hepatitis C virus
































159

7232019 mono100B-8


































160

7232019 mono100B-8


Hepatitis C virus
































161

7232019 mono100B-8


































162

7232019 mono100B-8


Hepatitis C virus


































163

7232019 mono100B-8


































164

7232019 mono100B-8


Hepatitis C virus






























165

7232019 mono100B-8



































166

7232019 mono100B-8


Hepatitis C virus





























167

7232019 mono100B-8



























7232019 mono100B-8


Hepatitis C virus










(b) Smoking





143

7232019 mono100B-8





















(a) Cohort studies






144

7232019 mono100B-8


Hepatitis C virus






(a) Cohort studies







145

7232019 mono100B-8















146

7232019 mono100B-8


Hepatitis C virus












147

7232019 mono100B-8




(c) Meta-analyses











148

7232019 mono100B-8


Hepatitis C virus



223 Other cancers

(a) Leukaemias















149

7232019 mono100B-8










See able 41


(a) Core protein







(a) p7



150

7232019 mono100B-8


Hepatitis C virus

(b) NS2


Jirasko et al 2008)

(c) NS3



(d) NS4A



151







Apoptosis


Cell entry









Oxydative stress






7232019 mono100B-8



(e) NS4B



(f) NS5A


(g) NS5B





See able 41






152

7232019 mono100B-8


Hepatitis C virus



(a) Core protein















153

7232019 mono100B-8




(b) NS2


(c) NS3-4A



(d) NS5A












154

7232019 mono100B-8


Hepatitis C virus

















155

7232019 mono100B-8















156

7232019 mono100B-8


Hepatitis C virus

















157

7232019 mono100B-8









47 Synthesis





5 Evaluation




References




158

7232019 mono100B-8


Hepatitis C virus
































159

7232019 mono100B-8


































160

7232019 mono100B-8


Hepatitis C virus
































161

7232019 mono100B-8


































162

7232019 mono100B-8


Hepatitis C virus


































163

7232019 mono100B-8


































164

7232019 mono100B-8


Hepatitis C virus






























165

7232019 mono100B-8



































166

7232019 mono100B-8


Hepatitis C virus





























167

7232019 mono100B-8



























7232019 mono100B-8





















(a) Cohort studies






144

7232019 mono100B-8


Hepatitis C virus






(a) Cohort studies







145

7232019 mono100B-8















146

7232019 mono100B-8


Hepatitis C virus












147

7232019 mono100B-8




(c) Meta-analyses











148

7232019 mono100B-8


Hepatitis C virus



223 Other cancers

(a) Leukaemias















149

7232019 mono100B-8










See able 41


(a) Core protein







(a) p7



150

7232019 mono100B-8


Hepatitis C virus

(b) NS2


Jirasko et al 2008)

(c) NS3



(d) NS4A



151







Apoptosis


Cell entry









Oxydative stress






7232019 mono100B-8



(e) NS4B



(f) NS5A


(g) NS5B





See able 41






152

7232019 mono100B-8


Hepatitis C virus



(a) Core protein















153

7232019 mono100B-8




(b) NS2


(c) NS3-4A



(d) NS5A












154

7232019 mono100B-8


Hepatitis C virus

















155

7232019 mono100B-8















156

7232019 mono100B-8


Hepatitis C virus

















157

7232019 mono100B-8









47 Synthesis





5 Evaluation




References




158

7232019 mono100B-8


Hepatitis C virus
































159

7232019 mono100B-8


































160

7232019 mono100B-8


Hepatitis C virus
































161

7232019 mono100B-8


































162

7232019 mono100B-8


Hepatitis C virus


































163

7232019 mono100B-8


































164

7232019 mono100B-8


Hepatitis C virus






























165

7232019 mono100B-8



































166

7232019 mono100B-8


Hepatitis C virus





























167

7232019 mono100B-8



























7232019 mono100B-8


Hepatitis C virus






(a) Cohort studies







145

7232019 mono100B-8















146

7232019 mono100B-8


Hepatitis C virus












147

7232019 mono100B-8




(c) Meta-analyses











148

7232019 mono100B-8


Hepatitis C virus



223 Other cancers

(a) Leukaemias















149

7232019 mono100B-8










See able 41


(a) Core protein







(a) p7



150

7232019 mono100B-8


Hepatitis C virus

(b) NS2


Jirasko et al 2008)

(c) NS3



(d) NS4A



151







Apoptosis


Cell entry









Oxydative stress






7232019 mono100B-8



(e) NS4B



(f) NS5A


(g) NS5B





See able 41






152

7232019 mono100B-8


Hepatitis C virus



(a) Core protein















153

7232019 mono100B-8




(b) NS2


(c) NS3-4A



(d) NS5A












154

7232019 mono100B-8


Hepatitis C virus

















155

7232019 mono100B-8















156

7232019 mono100B-8


Hepatitis C virus

















157

7232019 mono100B-8









47 Synthesis





5 Evaluation




References




158

7232019 mono100B-8


Hepatitis C virus
































159

7232019 mono100B-8


































160

7232019 mono100B-8


Hepatitis C virus
































161

7232019 mono100B-8


































162

7232019 mono100B-8


Hepatitis C virus


































163

7232019 mono100B-8


































164

7232019 mono100B-8


Hepatitis C virus






























165

7232019 mono100B-8



































166

7232019 mono100B-8


Hepatitis C virus





























167

7232019 mono100B-8



























7232019 mono100B-8















146

7232019 mono100B-8


Hepatitis C virus












147

7232019 mono100B-8




(c) Meta-analyses











148

7232019 mono100B-8


Hepatitis C virus



223 Other cancers

(a) Leukaemias















149

7232019 mono100B-8










See able 41


(a) Core protein







(a) p7



150

7232019 mono100B-8


Hepatitis C virus

(b) NS2


Jirasko et al 2008)

(c) NS3



(d) NS4A



151







Apoptosis


Cell entry









Oxydative stress






7232019 mono100B-8



(e) NS4B



(f) NS5A


(g) NS5B





See able 41






152

7232019 mono100B-8


Hepatitis C virus



(a) Core protein















153

7232019 mono100B-8




(b) NS2


(c) NS3-4A



(d) NS5A












154

7232019 mono100B-8


Hepatitis C virus

















155

7232019 mono100B-8















156

7232019 mono100B-8


Hepatitis C virus

















157

7232019 mono100B-8









47 Synthesis





5 Evaluation




References




158

7232019 mono100B-8


Hepatitis C virus
































159

7232019 mono100B-8


































160

7232019 mono100B-8


Hepatitis C virus
































161

7232019 mono100B-8


































162

7232019 mono100B-8


Hepatitis C virus


































163

7232019 mono100B-8


































164

7232019 mono100B-8


Hepatitis C virus






























165

7232019 mono100B-8



































166

7232019 mono100B-8


Hepatitis C virus





























167

7232019 mono100B-8



























7232019 mono100B-8


Hepatitis C virus












147

7232019 mono100B-8




(c) Meta-analyses











148

7232019 mono100B-8


Hepatitis C virus



223 Other cancers

(a) Leukaemias















149

7232019 mono100B-8










See able 41


(a) Core protein







(a) p7



150

7232019 mono100B-8


Hepatitis C virus

(b) NS2


Jirasko et al 2008)

(c) NS3



(d) NS4A



151







Apoptosis


Cell entry









Oxydative stress






7232019 mono100B-8



(e) NS4B



(f) NS5A


(g) NS5B





See able 41






152

7232019 mono100B-8


Hepatitis C virus



(a) Core protein















153

7232019 mono100B-8




(b) NS2


(c) NS3-4A



(d) NS5A












154

7232019 mono100B-8


Hepatitis C virus

















155

7232019 mono100B-8















156

7232019 mono100B-8


Hepatitis C virus

















157

7232019 mono100B-8









47 Synthesis





5 Evaluation




References




158

7232019 mono100B-8


Hepatitis C virus
































159

7232019 mono100B-8


































160

7232019 mono100B-8


Hepatitis C virus
































161

7232019 mono100B-8


































162

7232019 mono100B-8


Hepatitis C virus


































163

7232019 mono100B-8


































164

7232019 mono100B-8


Hepatitis C virus






























165

7232019 mono100B-8



































166

7232019 mono100B-8


Hepatitis C virus





























167

7232019 mono100B-8



























7232019 mono100B-8




(c) Meta-analyses











148

7232019 mono100B-8


Hepatitis C virus



223 Other cancers

(a) Leukaemias















149

7232019 mono100B-8










See able 41


(a) Core protein







(a) p7



150

7232019 mono100B-8


Hepatitis C virus

(b) NS2


Jirasko et al 2008)

(c) NS3



(d) NS4A



151







Apoptosis


Cell entry









Oxydative stress






7232019 mono100B-8



(e) NS4B



(f) NS5A


(g) NS5B





See able 41






152

7232019 mono100B-8


Hepatitis C virus



(a) Core protein















153

7232019 mono100B-8




(b) NS2


(c) NS3-4A



(d) NS5A












154

7232019 mono100B-8


Hepatitis C virus

















155

7232019 mono100B-8















156

7232019 mono100B-8


Hepatitis C virus

















157

7232019 mono100B-8









47 Synthesis





5 Evaluation




References




158

7232019 mono100B-8


Hepatitis C virus
































159

7232019 mono100B-8


































160

7232019 mono100B-8


Hepatitis C virus
































161

7232019 mono100B-8


































162

7232019 mono100B-8


Hepatitis C virus


































163

7232019 mono100B-8


































164

7232019 mono100B-8


Hepatitis C virus






























165

7232019 mono100B-8



































166

7232019 mono100B-8


Hepatitis C virus





























167

7232019 mono100B-8



























7232019 mono100B-8


Hepatitis C virus



223 Other cancers

(a) Leukaemias















149

7232019 mono100B-8










See able 41


(a) Core protein







(a) p7



150

7232019 mono100B-8


Hepatitis C virus

(b) NS2


Jirasko et al 2008)

(c) NS3



(d) NS4A



151







Apoptosis


Cell entry









Oxydative stress






7232019 mono100B-8



(e) NS4B



(f) NS5A


(g) NS5B





See able 41






152

7232019 mono100B-8


Hepatitis C virus



(a) Core protein















153

7232019 mono100B-8




(b) NS2


(c) NS3-4A



(d) NS5A












154

7232019 mono100B-8


Hepatitis C virus

















155

7232019 mono100B-8















156

7232019 mono100B-8


Hepatitis C virus

















157

7232019 mono100B-8









47 Synthesis





5 Evaluation




References




158

7232019 mono100B-8


Hepatitis C virus
































159

7232019 mono100B-8


































160

7232019 mono100B-8


Hepatitis C virus
































161

7232019 mono100B-8


































162

7232019 mono100B-8


Hepatitis C virus


































163

7232019 mono100B-8


































164

7232019 mono100B-8


Hepatitis C virus






























165

7232019 mono100B-8



































166

7232019 mono100B-8


Hepatitis C virus





























167

7232019 mono100B-8



























7232019 mono100B-8










See able 41


(a) Core protein







(a) p7



150

7232019 mono100B-8


Hepatitis C virus

(b) NS2


Jirasko et al 2008)

(c) NS3



(d) NS4A



151







Apoptosis


Cell entry









Oxydative stress






7232019 mono100B-8



(e) NS4B



(f) NS5A


(g) NS5B





See able 41






152

7232019 mono100B-8


Hepatitis C virus



(a) Core protein















153

7232019 mono100B-8




(b) NS2


(c) NS3-4A



(d) NS5A












154

7232019 mono100B-8


Hepatitis C virus

















155

7232019 mono100B-8















156

7232019 mono100B-8


Hepatitis C virus

















157

7232019 mono100B-8









47 Synthesis





5 Evaluation




References




158

7232019 mono100B-8


Hepatitis C virus
































159

7232019 mono100B-8


































160

7232019 mono100B-8


Hepatitis C virus
































161

7232019 mono100B-8


































162

7232019 mono100B-8


Hepatitis C virus


































163

7232019 mono100B-8


































164

7232019 mono100B-8


Hepatitis C virus






























165

7232019 mono100B-8



































166

7232019 mono100B-8


Hepatitis C virus





























167

7232019 mono100B-8



























7232019 mono100B-8


Hepatitis C virus

(b) NS2


Jirasko et al 2008)

(c) NS3



(d) NS4A



151







Apoptosis


Cell entry









Oxydative stress






7232019 mono100B-8



(e) NS4B



(f) NS5A


(g) NS5B





See able 41






152

7232019 mono100B-8


Hepatitis C virus



(a) Core protein















153

7232019 mono100B-8




(b) NS2


(c) NS3-4A



(d) NS5A












154

7232019 mono100B-8


Hepatitis C virus

















155

7232019 mono100B-8















156

7232019 mono100B-8


Hepatitis C virus

















157

7232019 mono100B-8









47 Synthesis





5 Evaluation




References




158

7232019 mono100B-8


Hepatitis C virus
































159

7232019 mono100B-8


































160

7232019 mono100B-8


Hepatitis C virus
































161

7232019 mono100B-8


































162

7232019 mono100B-8


Hepatitis C virus


































163

7232019 mono100B-8


































164

7232019 mono100B-8


Hepatitis C virus






























165

7232019 mono100B-8



































166

7232019 mono100B-8


Hepatitis C virus





























167

7232019 mono100B-8



























7232019 mono100B-8



(e) NS4B



(f) NS5A


(g) NS5B





See able 41






152

7232019 mono100B-8


Hepatitis C virus



(a) Core protein















153

7232019 mono100B-8




(b) NS2


(c) NS3-4A



(d) NS5A












154

7232019 mono100B-8


Hepatitis C virus

















155

7232019 mono100B-8















156

7232019 mono100B-8


Hepatitis C virus

















157

7232019 mono100B-8









47 Synthesis





5 Evaluation




References




158

7232019 mono100B-8


Hepatitis C virus
































159

7232019 mono100B-8


































160

7232019 mono100B-8


Hepatitis C virus
































161

7232019 mono100B-8


































162

7232019 mono100B-8


Hepatitis C virus


































163

7232019 mono100B-8


































164

7232019 mono100B-8


Hepatitis C virus






























165

7232019 mono100B-8



































166

7232019 mono100B-8


Hepatitis C virus





























167

7232019 mono100B-8



























7232019 mono100B-8


Hepatitis C virus



(a) Core protein















153

7232019 mono100B-8




(b) NS2


(c) NS3-4A



(d) NS5A












154

7232019 mono100B-8


Hepatitis C virus

















155

7232019 mono100B-8















156

7232019 mono100B-8


Hepatitis C virus

















157

7232019 mono100B-8









47 Synthesis





5 Evaluation




References




158

7232019 mono100B-8


Hepatitis C virus
































159

7232019 mono100B-8


































160

7232019 mono100B-8


Hepatitis C virus
































161

7232019 mono100B-8


































162

7232019 mono100B-8


Hepatitis C virus


































163

7232019 mono100B-8


































164

7232019 mono100B-8


Hepatitis C virus






























165

7232019 mono100B-8



































166

7232019 mono100B-8


Hepatitis C virus





























167

7232019 mono100B-8



























7232019 mono100B-8




(b) NS2


(c) NS3-4A



(d) NS5A












154

7232019 mono100B-8


Hepatitis C virus

















155

7232019 mono100B-8















156

7232019 mono100B-8


Hepatitis C virus

















157

7232019 mono100B-8









47 Synthesis





5 Evaluation




References




158

7232019 mono100B-8


Hepatitis C virus
































159

7232019 mono100B-8


































160

7232019 mono100B-8


Hepatitis C virus
































161

7232019 mono100B-8


































162

7232019 mono100B-8


Hepatitis C virus


































163

7232019 mono100B-8


































164

7232019 mono100B-8


Hepatitis C virus






























165

7232019 mono100B-8



































166

7232019 mono100B-8


Hepatitis C virus





























167

7232019 mono100B-8



























7232019 mono100B-8


Hepatitis C virus

















155

7232019 mono100B-8















156

7232019 mono100B-8


Hepatitis C virus

















157

7232019 mono100B-8









47 Synthesis





5 Evaluation




References




158

7232019 mono100B-8


Hepatitis C virus
































159

7232019 mono100B-8


































160

7232019 mono100B-8


Hepatitis C virus
































161

7232019 mono100B-8


































162

7232019 mono100B-8


Hepatitis C virus


































163

7232019 mono100B-8


































164

7232019 mono100B-8


Hepatitis C virus






























165

7232019 mono100B-8



































166

7232019 mono100B-8


Hepatitis C virus





























167

7232019 mono100B-8



























7232019 mono100B-8















156

7232019 mono100B-8


Hepatitis C virus

















157

7232019 mono100B-8









47 Synthesis





5 Evaluation




References




158

7232019 mono100B-8


Hepatitis C virus
































159

7232019 mono100B-8


































160

7232019 mono100B-8


Hepatitis C virus
































161

7232019 mono100B-8


































162

7232019 mono100B-8


Hepatitis C virus


































163

7232019 mono100B-8


































164

7232019 mono100B-8


Hepatitis C virus






























165

7232019 mono100B-8



































166

7232019 mono100B-8


Hepatitis C virus





























167

7232019 mono100B-8



























7232019 mono100B-8


Hepatitis C virus

















157

7232019 mono100B-8









47 Synthesis





5 Evaluation




References




158

7232019 mono100B-8


Hepatitis C virus
































159

7232019 mono100B-8


































160

7232019 mono100B-8


Hepatitis C virus
































161

7232019 mono100B-8


































162

7232019 mono100B-8


Hepatitis C virus


































163

7232019 mono100B-8


































164

7232019 mono100B-8


Hepatitis C virus






























165

7232019 mono100B-8



































166

7232019 mono100B-8


Hepatitis C virus





























167

7232019 mono100B-8



























7232019 mono100B-8









47 Synthesis





5 Evaluation




References




158

7232019 mono100B-8


Hepatitis C virus
































159

7232019 mono100B-8


































160

7232019 mono100B-8


Hepatitis C virus
































161

7232019 mono100B-8


































162

7232019 mono100B-8


Hepatitis C virus


































163

7232019 mono100B-8


































164

7232019 mono100B-8


Hepatitis C virus






























165

7232019 mono100B-8



































166

7232019 mono100B-8


Hepatitis C virus





























167

7232019 mono100B-8



























7232019 mono100B-8


Hepatitis C virus
































159

7232019 mono100B-8


































160

7232019 mono100B-8


Hepatitis C virus
































161

7232019 mono100B-8


































162

7232019 mono100B-8


Hepatitis C virus


































163

7232019 mono100B-8


































164

7232019 mono100B-8


Hepatitis C virus






























165

7232019 mono100B-8



































166

7232019 mono100B-8


Hepatitis C virus





























167

7232019 mono100B-8



























7232019 mono100B-8


































160

7232019 mono100B-8


Hepatitis C virus
































161

7232019 mono100B-8


































162

7232019 mono100B-8


Hepatitis C virus


































163

7232019 mono100B-8


































164

7232019 mono100B-8


Hepatitis C virus






























165

7232019 mono100B-8



































166

7232019 mono100B-8


Hepatitis C virus





























167

7232019 mono100B-8



























7232019 mono100B-8


Hepatitis C virus
































161

7232019 mono100B-8


































162

7232019 mono100B-8


Hepatitis C virus


































163

7232019 mono100B-8


































164

7232019 mono100B-8


Hepatitis C virus






























165

7232019 mono100B-8



































166

7232019 mono100B-8


Hepatitis C virus





























167

7232019 mono100B-8



























7232019 mono100B-8


































162

7232019 mono100B-8


Hepatitis C virus


































163

7232019 mono100B-8


































164

7232019 mono100B-8


Hepatitis C virus






























165

7232019 mono100B-8



































166

7232019 mono100B-8


Hepatitis C virus





























167

7232019 mono100B-8



























7232019 mono100B-8


Hepatitis C virus


































163

7232019 mono100B-8


































164

7232019 mono100B-8


Hepatitis C virus






























165

7232019 mono100B-8



































166

7232019 mono100B-8


Hepatitis C virus





























167

7232019 mono100B-8



























7232019 mono100B-8


































164

7232019 mono100B-8


Hepatitis C virus






























165

7232019 mono100B-8



































166

7232019 mono100B-8


Hepatitis C virus





























167

7232019 mono100B-8



























7232019 mono100B-8


Hepatitis C virus






























165

7232019 mono100B-8



































166

7232019 mono100B-8


Hepatitis C virus





























167

7232019 mono100B-8



























7232019 mono100B-8



































166

7232019 mono100B-8


Hepatitis C virus





























167

7232019 mono100B-8



























7232019 mono100B-8


Hepatitis C virus





























167

7232019 mono100B-8



























7232019 mono100B-8



























Documents

mono100B-8