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1、Human HerpesvirusesMolecular virology reactivation from latency Smart virus, big but “small” virusKaposis sarcoma associated herpesvirus(HHV8)Human viruses with oncogenic potentialTumor VirusChronically Infected (millions US)PersistenceType of TumorAIDS RelatedHPV20 (6.6%)Mostly transientCervical an
2、d PenileYesEBV228 (95%)LifelongIM, PTLD, NPC, BL, Non- HD, GCYesKSHV95%) 3 subfamilies (a, b, g)Gammaherpesviruses These viruses were initially grouped together because of their ability to drive the proliferation of latently-infected lymphocytes. EBV and KSHV naturally infect humans.Dogma: LCVs are
3、restricted to Old World primates (human, rhesus, baboon, etc.).Which of the following is NOT an Old World primate?ABCDEWhich of the following is NOT an Old World primate?DThe marmoset is a New World primate. The recent identification of a transforming marmoset lympho- cryptovirus is challenging the
4、dogma that these viruses are restricted to Old World primates.EBV genome structure 172 kb 4 internal repeats Flanked by terminal repeats 5 unique coding sequencesClinical correlation: infectious mononucleosis Primary infection with EBV is usually asymptomatic but, “mono” develops in some individuals
5、 after 1-2 months (age, inoculum). Symptoms: fatigue and sore throat Signs: fever and enlargement of lymph nodes, liver, and spleen Distinct transcription programs are used by EBV during latent infection (same genome, different gene products). The growth program is the most promiscuous in terms of g
6、ene expression and probably exists to expand the initial population of infected cells.Thorley- Lawson NEJM 2004Thorley- Lawson NEJM 2004 Distinct transcription programs are used by EBV during latent infection (same genome, different gene products). The growth program is the most promiscuous in terms
7、 of gene expression and probably exists to expand the initial population of infected cells. The growth program is dangerous (think lymphoma).Thorley- Lawson NEJM 2004 Distinct transcription programs are used by EBV during latent infection (same genome, different gene products). The growth program is
8、 the most promiscuous in terms of gene expression and probably exists to expand the initial population of infected cells. The growth program is dangerous, but very antigenic!Clinical correlation: infectious mononucleosis Infected B cells are clonally expanded during acute disease up to 80% of circul
9、ating WBCs are reactive CD8 T cells (Downey cells). Socioeconomic factors: infection is typically at an early age in “developing” countries. In USA: Students entering college 75% seropositive Exiting college nearly 100% seropositiveTumorSubtypeTypical latent periodEBV positivityLatent viral antigen
10、expressionBurkitts lymphomaEndemic Sporadic AIDS-associated3-8 years post-EBV 3-8 years post-EBV 3-8 years post-HIV100% 15-85% 30-40%EBNA1+Nasopharyngeal carcinomaPoorly/non- differentiated30 years post-EBV100%EBNA1+, LMP1+/-, LMP2+Hodgkins diseasemc/ld ns30 years post-EBV 10 years post EBV80-90% 30
11、%EBNA1+, LMP1+, LMP2+Immunoblastic lymphomaFatal IM Tr-associated Tr-associated AIDS-associated1 year post-tr 5-10 years post-HIV100% 100% 100% 70-80%EBNA 1, 2, 3A, 3B, 3C, LP+, LMP1+, LMP2+adapted from Fields Virologygrowth programEBV-associated malignanciesEBV latency types 2. Capsid transpotation
12、; 3. Vhs degrades mRNA 4. VP16 encoded by UL48 localized into nucleus; 5. Viral DNA circularizes 6. Alpha gene expression; 7 Alpha transactivates Beta; 8. Beta proteins are involved In replicating viral DNA; 9. Viral DNA synthesis stimulates Gamma expression 10. Gamma-assembling the capsid; 11. Vira
13、l DNA encapsidated; 12. EgressStages of HSV infection of the host HSV is introduced onto a mucosal surface or a break in the skin Virus replicates productively or establishes a latent infection Viral reactivation and sheddingEstablishment of viral latency HSV can establish latency in neuron mechanis
14、m for establishment of latency1. Lack of nuclear forms of host factors necessary for alpha gene expression.2. Hormonally regulated repression of viral gene expression3. LAT-mediated repression of alpha gene expressionReactivation of virus from latency Injury Physical or emotional stress Hormonal imb
15、alance Exposure to UV light Hyperthermia Menstruation Alpha Beta GammaA, Primary herpes gingivostomatitis. B, Herpes simplex virus establishes latent infection and can recur from the trigeminal ganglia. From Medical Microbiology, 4th ed., Murray, Rosenthal, Kobayashi reactivation from latencyThank you
