VirologyHemorrhagic Fever Viruses

· Arbovirus - A class of viruses transmitted to humans by arthropods such as mosquitoes and ticks. The first two letters of the words arthropod' and borne, make up the 'arbo' that now designates this group of viruses as arthropod-borne· Zoonosis - A disease of animals, such as rabies or psittacosis, that can be transmitted to humans.· Vector – any organism that is capable of spreading viral disease.· Reservoirs - A reservoir host or reservoir of infection, an alternate or passive host or carrier that harbours pathogenic

organisms, without injury to itself and serves as a source from which other individuals can be infected, reservoir must maintain and amplify the virus.

· Filoviruses· Are filamentous, enveloped, (-)ssRNA.· The Marburg and Ebola viruses are filoviruses. (used to be called Rhapdoviridae)· Filoviruses cause severe or fatal hemorrhagic fevers and are endemic in Africa.· Structure & Replication· (-)ssRNA encoding 7 proteins, virions from enveloped filaments with diameter of 80nm but can

assume other shapes, they can be 800-1400nm long.· Helical nucleocapsid enclosed by envelope containing 1 glycoprotein· Replicates in cytoplasm like rhapdovirus.· Pathogenesis· Replicates well in monocytes, macrophage, DCs, and others. Replication in monocytes elicits a cytokine storm of

proinflammatory cytokines similar to sepsis.· Cytopathogenesis causes extensive tissue necrosis of parenchymal cells in liver, spleen, lymph nodes, and lungs.· Ebola glycoprotein leads to endothelial cell damage thus vascular injury. Widespread hemorrhage causes edema and

hypovolemic shock.· The soluble form of the glycoprotein can be shed and inhibit neutrophil activation, block antibody action as well as inhibit

interferon production and action( so inhibits innate and humoral immunity).· Epidemiology· Marburg virus came from African green monkeys and Ebola from a river in Congo. · Bats and monkeys are reservoirs for these viruses. Ebola so lethal it eliminates pop. Before it can be spread · Contact with these animals, infected blood or secretions are infective.· Clinical· Marburg and Ebola are the most sever causes of viral hemorrhagic fevers.· Starts as flulike symptoms(headache, myalgia) then within a few days nausea, vomiting, and diarrhea (maybe rash)develop.

Subsequently hemorrhage from multiple sites(especially GI) and death occur in as many as 90% of patients.· Flulike nause, vomiting, diarrhea Hemorrhage(usually GI) death· Laboratory Diagnosis· All specimens must be carefully handled and requires level 4 isolation procedures that aren’t regularly availale.· Marburg – grows rapidly in tissue culture(vero cells)· Ebola – animal (guinea pig) inoculation may be necessary to recover Ebola virus, so culturing is hard.· Infected cells have large eosinophilic cytoplasmic inclusions.· Immunofluorescence used to detect viral antigens in tissue or antifilovirus IgG or IgM· ELISA used to detect antigens in fluids or antifilovirus IgG or IgM· RT-PCR of secretions can be used to confirm diagnosis and minimize handling of samples.· Treatment, Prevention, Control· Infected patients should be quarantined and infected animals killed.· Antibody-containing serum and interferon therapy have been tried.· Level 4 isolation required for handling.

Flavovirus· (+)ssRNA, icosahedral capsid, enveloped….arbovirus. slightly smaller than alphavirus

· Has two E viral glycoproteins E1 and E2, which pair and fold over creating a flat outer protein layer across the surface of the virion.· Most flaviviruses are related thus antibodies to one may neutralize another.· Replication· Attachment and penitration of flaviviruse is the same as alphaviruses(togaviruse), but the flaviviruses can also attach to the

Fc receptors on macrophages, monocytes, and other cells when it is coated by antibodies. The virion being coated by antibodies actually enhances the infectivity of these viruses by promoting uptake into these target cells.· (1) Virus enters cell by R’ mediated endocytosis. (2) The viral envelope then fuses w/ the membrane of the endosome on

acidification of the vesicle. Once released in cytoplasm the genomes bind (3) Ribosomes as mRNA. (4) the entire flavivirus genome is translated into a single polyprotein. (5) the polyprotein contains four nonstructural proteins( protease, RNA-dep-RNA polymerase..) as well as the capsid and the envelope structural proteins (6) acquire envelope by budding into intracellular vesicles (diff from alphavirus and is less efficient so may see may left in cell), (7) released by exocytosis or cell lysis. · The structural genes are at 5’-end so structural portion of the polyprotein is synthesized first and efficiently, leading to

increase in structural proteins, but decrease in the efficiency of nonstructural protein synthesis (like catalytic enzymes for DNA synth. Like alphavirus has at its 5’ end) and initiation of viral replication. Accounting for the time lag before detection of flavivirus replication.

· Flaviviruses replicate in the cytoplasm and bud into internal membranes.· Pathogenesis and Immunity· Death of infected cells result from combo of virus-induced insults such as large amount of viral RNA being replicated and

transcribed, blocking of cellular mRNA from being transcribed, increasing host cell membrane permeability, and preventing generation of proteins required for cellular repair and maintenance. · Since arboviruse often acquired from insect bites. Female mosquitoes acquire the flavivirus by taking blood meal from a

viremic vertebrate host. The host that the mosquito takes the blood from must be a “reservoir” that is have high enough viremia to infect the mosquito. The virus then infects epithelial cells of midgut, spreads through basal lamina of midgut to circulation of mosquito, and infect the salivary glands where it sets up a persistent infection and reaches high titers to be released in saliva.· On biting a host, the female mosquito regurgitates virus containing saliva into the bloodstream. The virus then circulates in

plasma until contacts susceptible cells such as vascular endothelial, monocytes, and macrophages.· The nature of the disease is dependent on the specific tissue tropism of the virus, the concentration of infecting virus, and

the individual’s response to the infection.· Can cause mild systemic disease, encephalitis, arthrogenic disease, or hemorrhagic disease.· Initial virema produces fever, chills, headaches, backaches, within 3-7 days. Most symptoms are thought to be mediated by

effects of interferon produced due to infection and these are considered mild systemic disease that usually doesn’t progress past this.· Secondary viremia can occur and infect brain, liver, skin and vasculature depending on the virus tropism.· Virus gets to the brain by infecting endothelial cells lining small vessels of the brain or choroid plexus.· The primary target cells of flaviviruses are the monocyte-macrophage lineage b/c they have Fc receptors for antibodies and

release cytokines on challenge. These non neutralizing Abs enhance activity 200-1000X.· Immune Response· Both humoral and cellular immunity are elicited and important to control primary infection.· dsRNA replicative intermediate of flavivirus is good inducer of IFN-β and IFN-α, these cytokines limit replication of the virus

and stimulate immune response accounting for flulike symptoms of primary viremia.

· Within 6 days IgM is produced and circulating, then IgG. These antibodies block the viremic spread and infection of other tissues. But remember non-neutralizing antibodies enhance the infectivity of flavivirus by binding mac’s w/ Fc R’ and enchancing uptake.· Inflammation from CMI can lead to encephalitis and · Hypersensitivity reactions like DTH mediate immune complex formation as well as activation of complement that can

weaken vasculature and cause rupture thus accounting for hemorrhagic symptoms.· Immune response to a related strain of dengue virus that do not prevent infection can promote immunopathogenesis,

leading to dengue hemorrhagic fever or dengue shock syndrome.· Epidemiology· Flavivirus is an arbovirus, to be an arbovirus: (1) infect vertebrates and invertebrates, (2)illicit sufficiently long viremia in

vertebrate host to allow other invertebrate vectors to get it (3)and be able to create persistent infection in arthropod salivary gland so other hosts can get it.· Humans are usually “dead-end hosts” b/c they don’t maintain persistent viremia in blood to allow mosquito to acquire it

from blood meal.· Aedes aegypti is the vector for yellow fever, dengue, and chikungunya. Humans are reservoir=urban cycle. These viruses are

maintained by Aedes mosquitoes in a sylvatic (jungle) cycle in which monkeys are natural host.·

Clinical· more humans are infected with flaviviruses than show significant,

characteristic symptoms, so incidence of disease is sporadic.· Chikungunya refers to crippling arthritis associated with serious disease

caused by these viruses.· Most flavivirus infections are relatively benign, but serious aseptic

meningitis and encephalitic or hemorrhagic disease can occur.· West Nile virus is part of this family and causes encephalitis.· Dengue and yellow fever viruses are the hemorrhagic viruses, dengue is

major worldwide problem although not endemic in USA the virus and vector are in central and northern South America.· Dengue fever is also known as break-bone fever, as symptoms are high

fever, headache, rash, and back and bone pain that last 1 wk. If person is rechallenged with another of the related strains it can cause dengue hemorrhagic fever(DHF) and dengue shock syndrome(DSS).· Non-neutralilzing antibodies enhance uptake of virus by macrophages

which cause memory T cells to become activated, release inflammatory cytokines and initiate hypersensitive reactions. These reactions lead to weakening and rupture of vasculature, internal bleeding, and loss of plasma, leading to shock symptoms.

· Yellow fever cause severe systemic disease with degeneration of the liver, kidney, and heart as well as hemorrhage. Liver involvement causes jaundice thus “yellow” fever, but massive GI hemorrhages(“black vomit”) may also occur. Mortality rate is ~ 50%.· Laboratory· Can be grown in both vertebrate and mosquito cell lines, but are difficult to isolate.· Infection is detected through cytopathologic studies, immunofluorescence, and hemadsorption of avian RBCs.· Detection anc characterization can be determined by RT-PCR of genomic RNA or viral mRNA in blood.· Hemagglutination inhibition, ELISA, and latex agglutination are serologic methods used for diagnosis.· Presence of specific IgM or seraconversion b/w acute and convalescent sera indicates infection.· Treatment, Prevention, Control· NO treatment exists other than supportive care· Easiest way to prevent spread is to eliminate its vector and breeding grounds.· Yellow fever is spread by A. aegypto mosquitos.· Live intradermal vaccine against yellow fever that gives lifelong immunityand

killed vaccines against encephalitis viruses are available.· Vaccine for dengue fever has not been produced due to danger of immune

enhancement upon second exposure.

BunyaviridaeBunya and Arena share several similarities. Both are (-)RNA enveloped viruses and zoonoses; most of Bunya are arbovirus but Arenaviridae are not. Most cause encephalitis or hemorrhagic disease.· Constitutes a supergroup of at least 200 enveloped, segmented, (-)RNA viruses.

Most are arboviruses spread by ticks, mosquitoes, or flies. Except hantaviruses (carried by rodent· Structure· Spherical 90-120nm diameter.· Envelope containing G1 and G2 glycoproteins and encloses 3 unique (-)dsRNA the larege(L), medium(M), and small(S). These

RNAs associate with proteins to form nucleocapsids.· Nucleocapsids include RNA-dep-RNA pol(Lprotein) and 2 nonstructural proteins (NSS and NSM). these viruses do NOT have

matrix protein which distinguishes them from other (-) RNA virus.· The different bunyaviridae can be distinguished by differences in the number and size of the virion proteins, the lengths of

the L, M, and S genome strands, and the transcription.· Replication – occurs in cytoplasm· (1)The G1 glycoprotein interacts with β integrins on the cells surface and virus is endocytosed (2) envelope fuses with

endosomal membrane upon acidification of the vesicle, (3) nucleocapsid is released into cytoplasm (4) bunyaviruses steal 5’ capped portion of host mRNA to prime synthesis of viral mRNA in cytoplasm unlike flu, (5) and mRNA and protein synthesis begin in the cytoplasm.(6) glycoprotein are synthesized and glycosylate in ER, (7) transferred to golgi, (8) where virions bud into golgi and are released by cell lysis or exocytosis.· M genome strand encodes – NSM , G1(viral attachment) and G2 proteins· L genome strande encodes – L protein(polymerase)· S genome strand encodes – N and NSS

· Replication of genome by L protein provides new templates for transcription, thus increasing rate of mRNA synthesis. For Phlebovirus, S strand is ambisense such that one protein is from + and the other from -· Pathogenesis· Most are arboviruses and thus use spread via arthropod vector. Virus in arthropod can be transmitted to its eggs.· Many bunyaviridae cause neuronal and glial damage and cerebral edema, leading to encephalitis, and in certain viremic

infections(Rift Valley Fever) hepatic necrosis. In Crimean-Congo hemorrhagic fever and Hantaan hemorrhagic disease the primary lesion involves the leakage of plasma and erythrocytes through the vascular endothelium, in Hantaan these changes are seen mostly in the kidney and are accompanied by hemorrhagic necrosis of kidney.· Unlike the other bunyaviruses rodents are the reservoir and vector for hantaviruses, and humans become infected by

breathing aerosols contaminated with infected urine. The virus initiates infection in lungs and remains there where it causes hemorrhagic tissue destruction and lethal pulmonary disease.· Epidemiology

· Most are infected by mosquitoes, ticks, or flies to rodents birds, and larger animals. Humans are infected when they enter the environment of the insect vector but are usually dead end hosts.· Transmission occurs during summer, but virus can survive in the ova of the mosquito through winter.· Many of the members of this virus family are found in South America, southeastern Europe, southeast Asia, and Africa, and

their names reflect their ecological niches. · Hantaviruses lack arthropod vector instead have rodents as reservoir and vector.·

· Should prob. Familiar w/ this chart at the bottom. B/c the members are mentioned in objectives.

Clincal· Usually cause nonspecific febrile, flulike, viremia related illness that is non-characteristic, and not severe.· Incubation is ~ 48 hr, fever last ~ 3 days· Encephalitis illnesses are sudden in onset after an incubation period of approximately 1 wk, and symptoms are fever,

headache, lethargy, and vomiting. Seizures occur in ~ 50% of patients. Illness lasts 10-14 days and death is rare less than 1% but seizure disorders occur in ~ 20%.· Hemorrhagic fevers, such as Rift valley, are characterized by petechial hemorrhages, ecchymosis, epistaxis, hematemesis,

melena, and bleeding of the gums. Death occurs in ~ 50% of patients with hemorrhagic phenomena.· Hantavirus pulmonary syndrome is a terrible disease, manifesting initially with prodrome including fever and muscle aches

but rapidly followed by interstitial pulmonary edema, respiratory failure, and death within days.

Transmission of California (La crosse) encephalitis virus, a type of Bunyavirus.

Laboratory· RT-PCR can be used to detect and identify bunyaviruses viral RNA.· Serologic tests confirm diagnosis of bunyanvirus infection.· Assays specific for IgM show acute infections· Seroconversion of IgG shows recent infection, but cross-reactions with viral genera are common

· ELISA used to detect antigen in clinical specimens with intense viremia like rift valley, renal syndrome, and Crimean-Congo hemorrhagic fever. ELISA can also be used to detect antigen in mosquitoes.· Treatment, Prevention, and Control· No specific therapy available.· Disease prevented by reducing contact b/w humans and vector. Vectors controlled through eliminating growth conditions,

spraying insecticides, installing netting or screening on windows and doors, wearing protective clothing, and controlling tick infestation. Rift Valley fever vaccines have been developed.

Arenaviruses· Arenaviruses include lymphocytic choriomenigitis(LCM) and hemorrhagic fever viruses such as Lassa, Junin, and Machupo

viruses. These viruses cause persistent infections in rodents and can be transmitted to humans as zoonoses (persistent in rodents).· Structure and Replication· Enveloped virus with 2 circular (-)ssRNA genome segments(L, S) and are seen in EM as “sandy” due to ribosomes.· Virions contain beaded nucleocapsid with 2 (-)ssRNA circles and a transcriptase. S=3400 nucleotides and L= 7200

nucleotides long· L strand is negative sense and encodes polymerase· S strand encodes nucleoprotein(N protein) and the glycoproteins but is ambisense. The N protein is transcribed directly from

ambisense RNA while the mRNA for the glycoproteins are transcribed from full length template of the genome, and as a result are produced late after genome replication. · Replication takes place in cytoplasm and they get their envelope from host cell plasma membrane.· Arenaviruses commonly cause persistent infections most likely due to inefficient transcription of glycoproteins and thus poor

virion assembly.· Pathogenesis· Infect macrophages and cause release of mediators of cell and vascular damage.· T cell-induced immunopahtologic effects exacerbate tissue destruction· Persistent infection of rodents result from neonatal infection and induction of immune tolerance.· Incubation ~ 10-14 days· Epidemiology· Most except viruses that cause LCM, are found in the tropics of Africa and South America and infect rodents chronically

leading to viral shedding in saliva, urine, and feces. · Virus that causes LCM infects hamsters and house mice, and in the USA is associated with pet hamsters and animals in

rodent-breeding facilities.· Lassa fever virus infects Mastomys natalensis, an African rodent and is rarely spread from human to human through contact

with infected secretions or body fluids.· Clinical Syndromes· Lymphocytic Choriomeningitis (LCM) – causes febrile illness with flulike myalgia more often than meningeal illness. ~ 10% of

infected get CNS symptoms. If the meningeal infection occurs it will start 10 days after the initial phase of the illness, with full recovery. Perivascular mononuclear infiltrates may be seen in neurons.· Lassa & Hemorrhagic Fevers – Lassa is endemic to West Africa, and Junin and Machupo viruses are found in Argentina and

Bolivia respectively.· These illnesses are characterized by fever, coagulopathy, petechiae, and occasional visceral hemorrhage as well as liver and

spleen necrosis, but NOT vasculitis. Hemorrhage, shock and occasionally cardiac and liver damage occur.· In contrast to LCM, hemorrhagic fevers cause no lesions of the CNS.· Pharyngitis, diarrhea, and vomiting (of blood)may be prevalent, especially in patients with Lassa fever.· Death occurs in ~ 50% of those infected (shock) with Lassa fever and less infected with other hemorrhagic viruses.· Diagnosis is suggested by recent travel to endemic areas.· Laboratory· Diagnosed on basis of serologic and genomic(RT_PCR) findings, b/c these viruses are too dangerous for routine isolation,

level 3 for LCM and level 4 for Lassa fever handling.· Throat specimesn can yield arenaviruses and urine is source of Lassa fever but not LCM.· Treatment, Prevention, and Controlb· Ribavirin has limited activity against arenaviruses and can be used to treat Lassa fever. But supportive therapy is usually the

most available for patients infected.

· Rodent-borne infections can be prevented by limiting contact with the vector and improved hygiene.HHV8(Kaposi Sarcoma)· Kaposi sarcoma is a vascular tumor that is otherwise rare in the United States, and is the most common neoplasm of AIDS

patients.· Lesions are characterized by proliferation of spindle shaped cells that express markers of both endothelial cells and smooth

muscle cells. There is also a large amount of slitlike vascular spaces suggesting they arise from primitive mesenchymal(precursors of vacular channels). · The lesions also have chronic inflammatory cell infiltrates, many have polyclonal or oligoclonal spindle cells although

advanced lesions are monoclonal, and the spindle cells are diploid and depend on growth factors for their proliferation suggesting that KS it is not a malignant tumor.· Pahtogenesis : Spindle cells produce pro-inflammatory and angiogenic factors, which recruit the inflammatory and

neovascular components of the lesion, and the later components supply the signals for survival and growth.· It is believed that HIV does not intitiate KS but instead is HHV8(KSHV), KSHV DNA is found in virtually all KS lesions, even in

those w/o HIV, and KSHV infections are predominately of spindle cells. KSHV infections are necessary for KS development but are not sufficient to alone cause KS, they require additional cofactors such as HIV.· The idea is that HIV suppreses immune system enough to allow dissemination of KSHV in host, or HIV infected T cells

produce cytokines and other proteins that promote spindle cell proliferation and survival.

· KSHV establishes latent infections and produces several proteins such as viral homologue of cyclin D and several inhibitors of p53, which will provide survival and growth advantages to allow proliferation.· Small population of KSHV goes through lytic cycle that produces numerous paracrine signaling molecules including viral

homologue of IL-6, several chemokines, and a constitutive GPCR. The chemokines elicit inflammatory infiltrates and the GPCR increases expression of VEGF which can promote angiogenesis. · KSHV is not restricted to endothelial cells. It’s a type of γ-herpesvirus and is thus phylogenetically related to lymphotropic

subfamily and can infect B cells, and in AIDS patients can cause cavity-based primary effusion lymphoma and in patients with Castleman disease can develop B cell lymphoproliferative disorders.· Clinically AIDS-KS is a lot different from sporadic KS. In AIDS the tumor is widespread, affecting skin, mucous membranes, GI,

lymph nodes, and lungs and are more aggressive than sporadic forms.· Lymphomas· AIDS related lymphomas can be divided into 3 groups on the basis of their location: systemic (80%), primary CNS, and body

cavity based lymphomas. · CNS is most common extra nodal site affected· Vast majority of these lymphomas are aggressive B cell tumors that present in an advanced stage esp. in CNS w/ non-

Hodgkin systemic lymphoma spread. · Patients with AIDS have higher levels of cytokines, some of which like IL-6 are growth factors for B cells.· EBV is thought to be a polyclonal mitogen for B cells and plays important role in half the systemic B cell lymphomas and

virtually all lymphomas primary in the CNS, also found in oral hairy leukoplakia due to latent EBV infections. · As discussed earlier the body cavity-based primary effusion lymphomas are thought to be caused by latent KSHV infections.· Latent HPV infections in AIDS patients are thought to cause squamous cell carcinoma of the cervix and its precursor lesions,

cervical dysplasia and carcinoma in situ.· Kaposi Sarcoma· There are 4 forms of KS that are recognized.· 1) Chronic KS(classical) characteristically occurs in older men of Europe and Mediterranean descent and is uncommon in the

USA. Chronic KS can be associated with an underlying second malignancy or altered immunity it is NOT associated with HIV. It present with multiple red to purple skin plaques or nodules, usually in the distal lower extremities, which slowly increase

in size and number and spread more proximally. These tumors are typically asymptomatic and remain localized to the skin and subcutaneous tissue.· 2) Lymphadenopathic KS(african or endemic) has same geographical distribution of Burkitt’s and is very prevalent in children.

It is NOT associated with HIV. Skin lesions are sparse and patients present with lymphadenopathy due to KS, and the tumor occasionally involves the viscera and is extremely aggressive. · 3) Transplant-associated KS occurs in the setting of solid organ transplant with its accompanying long term

immunosuppression. Is usually aggressive (even fatal) with nodal, mucosal, and visceral involvement. Lesions can regress when immunosuppressive therapy stops, but then organ rejection risk is higher.· 4) AIDS associated(epidemic) KS was originally found in 1/3 of AIDS patients but with the current regiments of

antivirals(HAART), KS is now found in less than 1%. AIDS associated KS can involve the lymph nodes or viscera and disseminates widely early in the course of the disease, but is usually not cause of death.· Pathogenesis· HHV8 or KSHV is a necessary requirement for KS development, but tumor progression also requires a cofactor, HIV is an

example of a cofactor. HHV8 and EBV are both γ-herpesviruses· KSHV induces a lytic and latent infection of endothelial cells both of which are important to the pathogenesis of KS. Lytic

infection leads to release of cytokines from infected T cells or from inflammatory cells recruited, these cytokines create a local production of factors to stimulate proliferation. A viral encoded constitutively active GPCR can induce VEGF production. IN latently infected cells KSHV proteins disrupts normal cellular proliferation controls and prevent apoptosis by producing viral p53 inhibitors and a viral homologue of cyclin D. · Thus latently infected cells have a growth advantage, and the lytic cells provide a local environment that favors proliferation.· In the early stages on a few cells are infected and with time virtually all spindle cells carry KSHV and these cells express both

cell markers for endothelial cells and smooth muscle cells.Red-purple macules proliferating spindle cells in nodular stage (visceral)

Morphology· In the indolent, classical disease of older men, 3 stages are recognized: patch, plaque, and nodule· Patches are red-purple macules typically confined to distal lower extremities. Histologically shows dilated irregular

endothelial cell-lined vascular spaces with interspersed lymphocytes, plasma cells, and macrophages. And the lesion can be difficult to distinguish from granulation tissue· Plaques: with time lesions spread proximally and become larger raised plaques that are composed of dermal accumulations

of dilated, jagged vascular channels lined and surrounded by plump spindle cells. RBCs, hemosiderin filled macrophages, and other mononuclear inflammatory cells are scattered b/w vascular channels.· Nodular: lesions become nodular and more distinctly neoplastic. These lesions are composed of sheets of plump,

proliferating spindle cells, mostly in the dermis or subcutaneous tissues, encompassing small vessels and slitlike spaces containing red cells. Marked hemorrhage, hemosideran pigment and mononuclear inflammation is present.. Round pink, cytoplasmic globules of uncertain nature as well as mitotic figures are commonly seen. The nodular stage often heralds nodal and visceral involvement, particularly in the African and AIDS associated KS.· Clinical Features· Most primary KSHV infections are asymptomatic.· Classic KS is larger restricted to the surface of the body, and surgical resection is good for excellent prognosis. Radiation can

be used for multiple lesions in a restricted area.· Chemo gives satisfactory results for most disseminated disease.· Lymphadenopathic KS can also be treated with chemotherapy or radiation with good results.· Immunosuppression associated KS often resolves with removal of immunosuppressive stimuli.· Antiretroviral therapy for HIV is usually helpful for AIDS associated KS with or without therapy targeted at KS lesions.

· IFN-α and angiogenesis inhibitors are variably effective.EBV· EBV is a member of the herpes family, and has been implicated in the pathogenesis of several human tumors: the African

from of Burkitt Lymphoma, B-cell lymphomas in immunosuppressed individuals, a subset of Hodgkin lymphoma, some rare T and NK cell lymphomas, nasopharyngeal, and some gastric carcinomas.· EBV is a DNA virus that infects B Cells and possibly epithelial cells of the oropharynx via the complement receptor CD21.· The EBV infection is latent in the B cell and immortalizes it allowing it to propagate indefinitely, EBV encodes several genes

such as LMP-1, that acts like a constitutively active CD40 receptor that stimulates B cell growth, usually when activated by helper T cell CD40L. CD40 activates NF-kB and JAK/STAT pathways that promote B cell proliferation. LMP-1 also prevents apoptosis by stimulating BCL-2. Thus cells infected with EBV can survive and proliferate freely of stimuli.· Another EBV gene encodes EBNA-2, which is a nuclear protein that mimics constitutively active Notch receptors and

transactivates several other host genes like cyclin D and src protoncogenes.· EBV also encodes viral cytokine IL-10, which can prevent macrophages and monocytes from activating T cells and is required

for EBV-dependent transformation of B cells.· In non-immuno compromised people the polyclonal B cell proliferation is controlled and the infection is usually

asymptomatic or produces self limited infectious mononucleosis episode. · Burkitt lymphoma is a neoplasm of B cells common in central Africa and New Guinea and EBV is strongly associated with it. · Although EBV is involved in the causation of Burkitt lymphoma other factors must be involved b/c EBV infection is not limited

to areas where Burkitt lymphoma is found but is ubiquitous; EBV is found in only 15% of sufferers of BL outside Africa; there are significant diff in the patterns of viral gene expression in EBV transformed but not tumorigenic B cell lines and Burkitt lymphoma-BL cells don’t have LMP-2 and EBNA2. EBV thus contributes in areas of endemic BL b/c infections w/ malaria impair the immune system and allow B cell proliferation. Eventually, T cell immunity against EBV like EBNA2 and LMP-1 eliminates most EBV infected B cells but a small # of cells downregulate expression and persist indefinitely even w/ normal immunity. Lymphoma cells arise after c-MYC activation. THUS, although non-African BL is triggered by mech other than EBV, both converge on similar oncogenic pathways. · The majority of EBV-transfomred cells express LMP-1 and EBNA-2, but neither are produced in Burkitt lymphoma. One

possible explanation for this is that B cell proliferation is sustained for some time before the host immune response is strong enough to eliminate EBV infected cells, the body eliminates all these cells except those that have down-regulated their expression of the targeted antigens and these cells persist indefinitely thus allowing lymphomas to emerge from these.· Lymphomas can only emerge upon acquisition of specific mutations most notably

translocation t(8;14) that activates c-MYC oncogene, or other mutations that activate c-MYC.· So EBV in Burkitt’s lymphoma is not directly oncogenic, but by acting as polyclonal B

cell mitogen sets the stage for acquisition of translocations and mutations that allow neoplastic growth. · EBV is a more direct cause of B cell lymphomas in immunocompromised

individuals such as AIDS patients or those receiving long-term immunosuppressive therapy.· At the beginning these tumors are polyclonal but develop into monoclonal

neoplasma and all express LMP-1 and EBNA2 in contrast to BL.· 100% of Nasopharygeal carcinoma contains EBV DNA and is thought to play

important role in the pathogenesis. In this case EBV is the starter of the tumor but it requires other environmental or genetic cofactors to develop into neoplasm. Patients develop IgA before tumor appears.· LMP-1 activates NF-kB but also induces expression of pro-angiogenic factors such as

VEGF, FGF2, MMP9, and COX2 that may contribute to oncogenesis.