A Glimpse on Viral Oncogenesis and Epidemiology of HIV/AIDS related Non-Hodgkin Lymphoma Weiming ZHU Nov 6, 2009

A Glimpse onA Glimpse on Viral Oncogenesis and EpidemiViral Oncogenesis and Epidemi

ology ology ofof

HIV/AIDS related HIV/AIDS related Non-Hodgkin LymphomaNon-Hodgkin Lymphoma

Weiming ZHUWeiming ZHUNov 6, 2009Nov 6, 2009

Non-Hodgkin LymphomaNon-Hodgkin Lymphoma

ICD-10 C82-C85ICD-10 C82-C85 C82 C82 Follicular [nodular] non-Hodgkin's lymphomaFollicular [nodular] non-Hodgkin's lymphoma C83 C83 Diffuse non-Hodgkin's lymphomaDiffuse non-Hodgkin's lymphoma

C83.3 Large cell (diffuse)C83.3 Large cell (diffuse) C83.7 Burkitt's tumourC83.7 Burkitt's tumour C84 C84 Peripheral and cutaneous T-cell lymphomasPeripheral and cutaneous T-cell lymphomas C85 C85 Other and unspecified types of non-Hodgkin's Other and unspecified types of non-Hodgkin's

lymphomalymphoma

Parkin DM, et al, Cancer incidence in five continents, 2002

Parkin DM, et al, Cancer incidence in five continents, 2002

Incidence of NHL, SEERIncidence of NHL, SEER

Incidence Rates by Race 2002-2006

Race/Ethnicity Male Female

All Races 23.5 per 100,000 men 16.4 per 100,000 women

White 24.4 per 100,000 men 17.2 per 100,000 women

Black 18.3 per 100,000 men 12.2 per 100,000 women

Asian/Pacific Islander 15.5 per 100,000 men 10.9 per 100,000 women

American Indian/Alaska Native a 11.8 per 100,000 men 10.0 per 100,000 women

Hispanic b 19.1 per 100,000 men 14.6 per 100,000 women

Mortality of NHL, SEERMortality of NHL, SEER

Death Rates by Race 2002-2006

Race/Ethnicity Male Female

All Races 9.0 per 100,000 men 5.7 per 100,000 women

White 9.3 per 100,000 men 5.9 per 100,000 women

Black 6.3 per 100,000 men 4.1 per 100,000 women

Asian/Pacific Islander 5.4 per 100,000 men 3.7 per 100,000 women

American Indian/Alaska Native a 5.2 per 100,000 men 4.4 per 100,000 women

Hispanic b 6.4 per 100,000 men 4.6 per 100,000 women

Estimated NHL in US, 2009Estimated NHL in US, 2009

New cases: 65,980New cases: 65,980 Deaths: 19,500 Deaths: 19,500

http://www.cancer.gov/cancertopics/types/non-hodgkinhttp://www.cancer.gov/cancertopics/types/non-hodgkin

Risk Factors of NHLRisk Factors of NHL

Occupational and environmental factorsOccupational and environmental factors

Pesticide : Occupational and environmentalPesticide : Occupational and environmental Lifestyle and personal factorsLifestyle and personal factors Tobacco and alcohol use, Dietary factors, BMITobacco and alcohol use, Dietary factors, BMI

Hair dyes, Hormonal and reproductive factors, Hair dyes, Hormonal and reproductive factors,

Physical activityPhysical activity

Family history and Genetic factorsFamily history and Genetic factors Family history, Genetic variation (SNP)Family history, Genetic variation (SNP)

DD. Alexander et al. Int. J. Cancer: 120, 1–39 (2007)

Risk Factors of NHLRisk Factors of NHL Infection & ImmunityInfection & Immunity

Example:Example: Burkitt Lymphoma Burkitt Lymphoma

First Epidemiological Report:First Epidemiological Report:Epidemiological evidence for causal relEpidemiological evidence for causal relationship between Epstein-Barr virus aationship between Epstein-Barr virus and Burkitt's lymphoma from Ugandan nd Burkitt's lymphoma from Ugandan prospective study prospective study

NatureNature 274, 756 - 761 (24 August 1978) 274, 756 - 761 (24 August 1978)

Glemser B. Mr Burkitt and Africa. 1970.Glemser B. Mr Burkitt and Africa. 1970.

HIV/AIDS related NHLHIV/AIDS related NHL

““Outbreak” in 1982Outbreak” in 1982

“ “The second unusual malignancy among this gThe second unusual malignancy among this group of young males” roup of young males”

Diffuse, Undifferentiated Non-Hodgkin’s Lymphoma aDiffuse, Undifferentiated Non-Hodgkin’s Lymphoma a

mong Homosexual Males -- United Statesmong Homosexual Males -- United States MMWR June 04, 1982 / 31(21);277-9MMWR June 04, 1982 / 31(21);277-9

HIV/AIDS related NHLHIV/AIDS related NHL

Lancet 1991; 337: 805–09

Lancet 1998; 351: 1833–39

HIV/AIDS associated NHLHIV/AIDS associated NHL Primary Effusion Lymphoma / PELPrimary Effusion Lymphoma / PEL ‘‘Solid’ lymphomas with serous effusions Solid’ lymphomas with serous effusions ‘‘Solid’ lymphomas without serous effusionsSolid’ lymphomas without serous effusions Large B-cell lymphoma arising in KSHV-associated MCD Large B-cell lymphoma arising in KSHV-associated MCD

Immunodeficiency-associated Burkitt Lymphoma-plasmacytImmunodeficiency-associated Burkitt Lymphoma-plasmacytoid lymphomaoid lymphoma

Primary central nervous system lymphomaPrimary central nervous system lymphoma DLBCL, immunoblastic-plasmacytoid lymphomaDLBCL, immunoblastic-plasmacytoid lymphoma KSHV/HHV8-positive PEL and its solid variantKSHV/HHV8-positive PEL and its solid variant Plasmablastic lymphoma of the oral cavity type PELPlasmablastic lymphoma of the oral cavity type PEL

A Carbone et al, Blood. 2009;113: 1213-1224A Carbone et al, Blood. 2009;113: 1213-1224

Burkitt Lymphoma. Burkitt Lymphoma. Ed Uthman, MD. , WikipediaEd Uthman, MD. , Wikipedia

H. Löffler, J. Rastetter, T. Haferlach. Atlas of Clinical Hematology 6ed.


Plasmablastic LymphomaPlasmablastic Lymphoma

Viral Oncogenesis of NHLViral Oncogenesis of NHL Epstein-Barr VirusEpstein-Barr Virus Kaposi Sarcoma-associated HerpesvirusKaposi Sarcoma-associated Herpesvirus

A Arvin et al, Human A Arvin et al, Human Herpesvirus. 2007.Herpesvirus. 2007.pp342. Fig. 22.1.pp342. Fig. 22.1.


Epstein-Barr VirusEpstein-Barr Virus

Epstein-Barr VirusEpstein-Barr Virus

Subfamily GammaherpesvirinaeSubfamily Gammaherpesvirinae Genus LymphocryptovirusGenus Lymphocryptovirus Formal Name:Formal Name: Human herpesvirus 4 / HHV-4Human herpesvirus 4 / HHV-4 Common Name:Common Name: Epstein-Barr virus / EBVEpstein-Barr virus / EBV

SeroepidemiologySeroepidemiology

Kenya, 94% of children are EBV seropositive by 3 yearKenya, 94% of children are EBV seropositive by 3 years of age (Moormann et al. 2005). similar in Nigeria (Mars of age (Moormann et al. 2005). similar in Nigeria (Martro et al. 2004) , Ethiopia (Tsega et al.1987). tro et al. 2004) , Ethiopia (Tsega et al.1987).

Children in Hong Kong were reported to be 61% EBV sChildren in Hong Kong were reported to be 61% EBV seropositive by 2 years (Chan et al. 2001)eropositive by 2 years (Chan et al. 2001)

Germany and USA between 45% and 47% (Martro et al.Germany and USA between 45% and 47% (Martro et al. 2004) 2004)

Transmission of EBVTransmission of EBV

General:General: SalivaSaliva Oropharyngeal secretionsOropharyngeal secretions

RareRare Blood TransfusionBlood Transfusion

Target Cells of EBVTarget Cells of EBV

MajorMajor B-lymphocytes B-lymphocytes Epithelial cellsEpithelial cells OtherOther T-cellsT-cells NK-cellsNK-cells Smooth Muscle CellsSmooth Muscle Cells Follicular Dendritic Cells (possible)Follicular Dendritic Cells (possible)

Molecular EpidemiologyMolecular Epidemiology EBV type 1EBV type 1 B95-8 cell line, a patient of infectious mononucleosis (IB95-8 cell line, a patient of infectious mononucleosis (I

M) , USAM) , USA EBV type 2EBV type 2 AG876 strain, a patient with endemic Burkitt’s lymphoAG876 strain, a patient with endemic Burkitt’s lympho

ma, Ghanama, Ghana Different in capacity of TransformationDifferent in capacity of Transformation Type 1: Transforms cells in cultureType 1: Transforms cells in culture Type 2: Poorly transforming, reactivates from Type 2: Poorly transforming, reactivates from latency latency

Molecular EpidemiologyMolecular Epidemiology Type 1 is the dominant strain in Western countriesType 1 is the dominant strain in Western countries A higher prevalence of Type 2 in South AmericaA higher prevalence of Type 2 in South America Relatively equal in some African countriesRelatively equal in some African countries (Zimber et al. 1986; Yao et al. 1991b; Gratama et al. 1994;(Zimber et al. 1986; Yao et al. 1991b; Gratama et al. 1994;

Falk et al. 1997: Young, 1987 #453). Falk et al. 1997: Young, 1987 #453).

Co-infection of Type 1 and Type 2Co-infection of Type 1 and Type 2 Less than 10% of adults tested in US and European High iLess than 10% of adults tested in US and European High i

n HIV-infected homosexual males and transplant recipien HIV-infected homosexual males and transplant recipientsnts

(Katz et al. 1988; Sixbey et al. 1989; Gratama et al. 1994; (Katz et al. 1988; Sixbey et al. 1989; Gratama et al. 1994; Yao et al. 1996).Yao et al. 1996).

Molecular EpidemiologyMolecular Epidemiology

Type 1 predominates in most EBV-Type 1 predominates in most EBV-associated malignancies :associated malignancies :

Nasopharyngeal carcinoma, Hodgkin’s Nasopharyngeal carcinoma, Hodgkin’s lymphoma, and Post-transplant lymphoma lymphoma, and Post-transplant lymphoma

Type 2 detected in tumors, particularlyType 2 detected in tumors, particularly

those arising in Men who have Sex with those arising in Men who have Sex with Men (MSM) and are HIV infected Men (MSM) and are HIV infected

A Tselis, HB Jenson. Epstein-Barr virus 2006.

Genome of EBVGenome of EBV

A Tselis, HB Jenson. Epstein-Barr virus 2006. pp22, Figure 1

Meyers C. 2007 AIDS-Associated Viral Oncogenesis, pp143 Figure 1

Latent InfectionLatent Infection

A Arvin et al, HA Arvin et al, Human Herpesvuman Herpesvirus. 2007.irus. 2007.pp380. Fig. 24.pp380. Fig. 24.1.1.

Latent InfectionLatent Infection

A Tselis, HB Jenson. Epstein-Barr virus 2006. pp24

Potential MechanismPotential Mechanism

Burkitt LymphomaBurkitt Lymphoma

EBNA-1 cooperate with c-mEBNA-1 cooperate with c-myc ?yc ?

Deregulate c-myc expressioDeregulate c-myc expression n

ARF – p53 pathway?ARF – p53 pathway?

http://www.benbest.com/health/cancer.html


DLBCL : DLBCL : LMP-1LMP-1 NFNFκκB, JNK, p38 pathway ?B, JNK, p38 pathway ? Knockdown LMP-1 from AIDS-DLBLC Knockdown LMP-1 from AIDS-DLBLC cell lines cell lines apoptosis apoptosis

AIDS-DLBCL : AIDS-DLBCL : MMonoclonalonoclonalPost-transplant DLBCL : Post-transplant DLBCL : mono/oligo/polyclonalmono/oligo/polyclonal

Potential genetic damage ?Potential genetic damage ?


NF-κB Pathway

http://www.abgab.com

JNK Pathway

EBV, HIV and NHLEBV, HIV and NHL


Kaposi Sarcoma-associated HerpesvirusKaposi Sarcoma-associated Herpesvirus

Kaposi Sarcoma-associated HerpesvirusKaposi Sarcoma-associated Herpesvirus

Chang et al. Chang et al. Identification of Herpesvirus-Like DNA Sequences in AIIdentification of Herpesvirus-Like DNA Sequences in AI

DS-Associated Kaposi's SarcomaDS-Associated Kaposi's Sarcoma Science 1994, 2669(5192):1865-1869Science 1994, 2669(5192):1865-1869..

Subfamily GammaherpesvirinaeSubfamily Gammaherpesvirinae Genus RhadinovirusGenus Rhadinovirus

Formal Name:Formal Name: Human herpesvirus 8 / HHV-8 Human herpesvirus 8 / HHV-8

Genome of KSHVGenome of KSHV


Target Cells of KSHVTarget Cells of KSHV Not yet fully characterizedNot yet fully characterized B-cells: B-cells: peripheral blood, primary effusion lymphomas (PEL), bperipheral blood, primary effusion lymphomas (PEL), b

ody-cavity based B-cell lymphomas (BCBL), multicentody-cavity based B-cell lymphomas (BCBL), multicentric Castleman’s disease (MCD), ric Castleman’s disease (MCD),

Flat endothelial cells:Flat endothelial cells: vascular spaces of Kaposi’s sarcoma (KS) lesions,vascular spaces of Kaposi’s sarcoma (KS) lesions, Typical KS Spindle CellsTypical KS Spindle Cells CD45+/CD68+ Monocytes in KSCD45+/CD68+ Monocytes in KS KeratinocytesKeratinocytes Epithelial CellsEpithelial Cells

Transmission of KSHVTransmission of KSHV

Sexual transmissionSexual transmission

Mother-to-child transmissionMother-to-child transmission

Salivary transmissionSalivary transmission

B Damania, JM Pipas. DNA Tumor Viruses 2009

SeroepidmeiologySeroepidmeiology

No gold-standard of antibody testNo gold-standard of antibody test Heterogeneity between different assaysHeterogeneity between different assays ORF73 / LANAORF73 / LANA

Africa with 30–60% Africa with 30–60% 3 to 10% in United States and Western Europe 3 to 10% in United States and Western Europe 4–35% Italy and Greece4–35% Italy and Greece

(Mediterranean area with higher incidence rates (Mediterranean area with higher incidence rates for classical or transplant-associated KS). for classical or transplant-associated KS).

SeroepidmeiologySeroepidmeiology

anti-LANA seropositivityanti-LANA seropositivity approximately 80% of KS approximately 80% of KS less than 5% of non-male-homosexual adults in the USless than 5% of non-male-homosexual adults in the US

A or Northern Europe A or Northern Europe (i.e., specificity of at least 95%) (Kedes et al., 1996; Gao (i.e., specificity of at least 95%) (Kedes et al., 1996; Gao

et al., 1996a,b; Simpson et al., 1996). et al., 1996a,b; Simpson et al., 1996).


Promotion of Cellular Growth and SurvivalPromotion of Cellular Growth and Survival Chromosome InstabilityChromosome Instability Suppress p53, pRbSuppress p53, pRb LANA-1, LANA-2, vIRF-1LANA-1, LANA-2, vIRF-1 Accelerate Cellular ProliferationAccelerate Cellular Proliferation vCyclinvCyclin Promote Cell SurvivalPromote Cell Survival vGPCR, vFLIP – NFvGPCR, vFLIP – NFκκB pathwayB pathway Induce growth factorsInduce growth factors IL-6, IL-8, VEGF etc.IL-6, IL-8, VEGF etc.

p53 Pathwayp53 Pathwaywww.abgab.comwww.abgab.com

Cyclins and Cell Cycle Regulation

www.abgab.comwww.abgab.com


Regulation of AngiogensisRegulation of Angiogensis (in KS-like lesions)(in KS-like lesions) Immune ModulationImmune Modulation Passive StrategyPassive Strategy de novode novo Infection: Infection: manipulating cytokine regulatory manipulating cytokine regulatory networknetwork

KSHV, HIV and NHLKSHV, HIV and NHL



Differential Diagnosis of Effusion LymphomaDifferential Diagnosis of Effusion Lymphoma

Louis M. Staudt, NEJM 2006, 354(23):2431-42

Epidemiologic Issues ?Epidemiologic Issues ?

Heterogeneity between different ethnics Heterogeneity between different ethnics ::

Caucasian Vs. Mongolia ?Caucasian Vs. Mongolia ? Prevalence of EBV and KSHV latent infecPrevalence of EBV and KSHV latent infec

tiontion Any prevention or intervention ?Any prevention or intervention ? Other VirusesOther Viruses Polyomavirus SV40 ?Polyomavirus SV40 ?

Thank You !Thank You !

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A Glimpse on Viral Oncogenesis and Epidemiology of HIV/AIDS related Non-Hodgkin Lymphoma Weiming ZHU Nov 6, 2009