INTR VIROLOGY BIOL 4190
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Date Created: 10/13/15
EPSTEINBARR VIRUS HHV4 EBV History EBV was discovered as a result of pioneering work in the 1950s by Denis Burkitt Burkitt identi ed a previously unrecognized form of cancer which affected the jaws of young African children and he made the crucial insight that the distribution of this common tumor now known as Burkitt s lymphoma appeared to be in uenced by climatic factors notably temperature and elevation His work was followed by Tony Epstein an English pathologist Epstein with his graduate student Yvonne Barr identified by electron microscopy a novel herpesvirus in lymphoma cell cultures This virus was named EpsteinBarr virus EBV and it had the ability to confer unlimited growth on peripheral blood B lymphocytes in tissue culture called immortalization Epidemiology EBV infects gt95 of the world s population by young adulthood In the Us and UK 50 of children are infected before age 5 Delay of infection until adolescence when the viral inoculum can be quite large exchange of saliva often results in the syndrome of infectious mononucleosis Close personal contact is usually required for transmission kissing disease The incubation period is estimated to be 30 50 days Viral excretion from the oropharynx occurs for months after primary infection and intermittently throughout life EBV can also be transmitted by blood transfusion or tissue transplantation Like herpes simplex virus Biology EBV is a member of the lymphocryptovirus genus of gammaherpesviruses Related viruses exist in all Old World primates These viruses share a tropism for B lymphocytes and have a propensity to oncogenicity EBV infects primary B lymphocytes which EBV latently infects with very high efficiency both in vivo and in vitro The virus triggers these cells to start to proliferate and then sustains their proliferation through the expression of specific growthpromoting genes Virus morphology is identical to that of other members of the herpesvirus family EBV has a double stranded DNA molecule of more than 172 kilobase pairs in length which encodes some 85 genes The EBV DNA genome is linear in its infectious form Upon entry into B lymphocytes the viral DNA circularizes within the cell nucleus to form extrachromosomal episomes via homologous recombination of terminal repeat sequences Viral attachment and entry virus receptors have been defined only for B lymphocytes where the complement receptor type 2 CR2 also called CD21 binds EBV The EBV envelope glycoprotein gp350 serves as attachment protein and interaction of the two molecules triggers endocytosis The HLA class II molecule on B cells serves as co receptor for EBV It binds EBV glycoprotein gp42 as a complex with two other viral glycoproteins gp85 homologue of HSV glycoprotein gH and gp25 homologue of gL to facilitate membrane fusion membrane protems LMIPs are expressedln latently mfeeteol eell llnes Flve of tlne mne Prl ls tlne vlral oneoprotem responslble for tlne majority of growth altenng effects of EBV on B lymplnoeytes EBV lytic cycle In ywa EBV replreatron oeeurs most emerently m eprtnelral eells However EBVreplreatron also oeeurs spontaneously m a small fractlon ofthe latently nknown al oug EBVreplreanon eanbe mggeredln afractlon of o u tln h B eells m won uslng phorbol ester a protem kmase Caetryat r or b tlns are atently lnfecte d y tlne EBVeneooleol BZLFl protem m Zm ZEBRA LIW l ll39c wlc M11er lnluclion ImmM L rlllllm lmmmllnll mm mmnlor cluh s nes mm H hpn sxm Kvl lplrgtrd Jhmu l AI l l I EBV l cclion 41mmmuinmmulmun mm mm mm 41w 5 I ilmun Inl39crumi crsiltlcIL39c l mvmn mmnm 01 LpubLhum Slumdd mmumm upuhvhmu 8 oo 0 930 0 0 o o zu damas V gt Recluw39hdl mm 1 urn Viral genome maintenance during latency oriP OriP is the origin of DNA synthesis for episoma lEBV DNA in latently infected B cells Its activity is absolutely dependent the expression of EBNA1Functions of oriPEBNAI include 1 genome replication 2 genome segregation to daughter cells Disease Associations Posttransplarlt lymphoproliferative aireme PTLD PTLD is a wellrecognized risk of immunosuppressive therapy associated with solid organ transplantation or Tcell depleted allogeneic bone marrow transplantation PTLD behaves aggressivel In organ transplanm reducing immunosuppression may lead to improved immunosurveillance and tumor regression Adoptive immunotherapy with EBV specific cytotoxic T cells may be effective as prophylaxis and treatment in bone marrow transplants Primary central nervous xystem lymphoma of AIDS PCNSL Tumors are almost 100 EBV associated The disease is usually fatal Within two months of diagnosis No adequate therapy is available Xlirlked lymphoproliferative aireme Duncan s syndrome XLP stems from an inherited maternally derived recessive genetic defect clinically manifest as three phenotypic expressions in b s 2 to 5 years of age the most common ofwhich is a fatal infectious mononucleosis Burkittlike lymphomas and persistent agammaglobulinemia are the other phenotypes Hodgkin 3 disease EBV DNA RNA and protein have been identi ed in the binucleate ReedStemberg cancer cell in about 4060 of cases in the US most frequently of the mixed cellularity subtype Burkitt s lymphoma BL is endemic in equatorial Africa where it accounts for 80 of all childhood cancers There is a characteristic anatomic distribution to jaw 72 and abdomen 56 Continuous reinfection with malaria causes polyconal B lymphocyte stimulation which together with malnutrition suppresses T cell responses An expanded number of EBVinfected proliferating B cells allows for higher probability of developing cytogenetic abnormalities Both endemic African and sporadic US Burkitt s lymphoma are characterized by cytogenetic alterations involving chromosomal t1 39 quot between clu 8 the myc protooncogene and chromosome 14 Ig heavy chain locus also more rarely chromosomes 2 22 Nasopharyngeal carcinoma NPC is one of the most common cancers in southern China with a peak incidence in the 5054 year age range Population based screening has validated the use of EBV serology for NPC detection in high risk groups in southern China Patients with an IgA response to EBV early antigen EA or viral capsid antigen VCA have a 30 fold greater risk of disease Chronic fatigue syndrome This entity is not related to EBV infection A small subset of patients may have abnormal serologic tests for EBV and other viruses Oral Hairy Leukoplakia of AIDS This wartlike lesion occurs primarily on lateral aspects of the tongue in HIVpositive patients It is an epithelialbased focus of EBV replication Exuberant viral replication makes OHL unique among EBV s clinical manifestations The lesions respond well to acyclovir but frequently recur once therapy is stopped 39 J for 5 of all hospitalizations of University of Wisconsin students and ranked fourth in cause of days lost due to illness in Army personnel The syndrome is manifest by sore throat malaise fever lymphadenopathy hepatosplenomegaly and atypical lymphocytosis gt10 atypicals on peripheral blood smear Rash is frequent in patients treated with ampicillin Complications include splenic rupture thrombocytopenia agranulocytosis hemolytic anemia orchitis and myocarditis KAPOSI SARCOMA HERPESVIRUS KSHV 0r HHV8 History Human herpesvirus 8 HHV8 was discovered by Yuan Chang and Patrick Moore in 1994 using KS tumor samples Moore and Chang used a method known as Representational Difference Analysis RDA to compare DNA samples prepared from KS tumors with DNA from KSnegative persons In the course of this analysis they found some DNA sequences that were present only in the KS tissues These turned out to be snippets of the genome of HHV8 Represemah39onnl Difference Analysis DNA mm mummy m nrsmmnn then K R Er quot1 M 11 um sequenns Hymn sham sequenns V m mgrsn sanA Meme picinn ennrhra n target Enidemiolo Current emdmce indicates HHVrB unhke the majunly er ether herpesmruses is nuts ubxqmluus human infecuun Sawing sereens furHHVrX lateney assumaled nudar anugen LANA have demunstmled anubudy m gater than 9 er semen as well as m pmpheml bland mununudar eeus and pmstau ussue Biolog The size ufHHVrB ls appmxsmately ms kbp and the lmar duuble mnded DNA generne urcmanzesbyns terrmns1 repats dunng the Lmnsmun te alalemplamd g erne There are 211225181 premeted epen Edmg flames HHVrB appars te have t V t ve genes 5 aeqmred are erther established human pmmrnmngmzs Dr eentnhute te zpupmsis the preeess ufpmgmmmed eeu dam Viral Lr is a secreted cylukme vlLr may mhance eeu pmhfemuun hy mhbmun ufnm39mal a eeu a e tesrs srgnahng The viral cyclin has 3621351 snnuanty tn the cellular Drlype eyehns pmlems mvulved m regulauun er eeu cycle A viral 011mm cnllpled reeepmr GCR gene wnh humulugy tn the cellular quot78 reeepter binds chemukmes and mhances prehremtmn er bmblasts Viral interfernn re wry rasmr IRF has humulugy tn 2 m y er cellular pmlems respunslble fur mla39fa39un sgnal Lmnsdummn lmpunanl m preventing cellular transformation as well as inducing cellular antiviral responses vIFR acts as a negative regulator of interferon signaling Diseases Kaposz39 Sarcoma KS is a multicentric neoplasm consisting of multiple vascular nodules in skin mucous membranes and viscera AIDSepidemic KS in contrast to classical or endemic forms is a disease predominantly of homosexual men with 96 of all cases occurring in that risk group Body cavity based primary e usion lymphomas KSHV is consistently found in this rare B cell lymphoma variant of AIDS which has distinctive genetic and morphologic features that distinguish them from other large cell immunoblastic lymphomas Most but not all are coinfected with EBV Latently infected cell lines have been established from these tumors and are the only cell culture system that can maintain the virus in vitro Castleman s Disease CD is a nonneoplastic lymphoproliferative disease CD seems to occur in a setting of interleukin 6 IL 6 overexpression
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