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Oncogenic viruses DNA viruses • Herpesviridae – Human Herpes Virus 8 (HHV8) a.k.a Kaposi’s sarcoma associated virus – Epstein-Barr virus (EBV) • Papovaviridae – human papilloma virus (HPV) • Hepadnaviridae – hepatitis B virus-(HBV) RNA viruses • Flaviviridae – (hepatitis C virus HCV) • Retroviridae – Human T-cell lymphotropic virus (HTLV type I) Why are they oncogenic? Viral genomes show the presence of several human gene homologues that are responsible for cellular transformation e.g. v-myc and c-myc (myc oncogene) or vIL6 and IL6 (interleukin 6) Overview of viral replication Human Herpes Virus 8 (HHV8) or Kaposi’s sarcoma associated virus KSHV Herpes virus family Type 1 - causes ‘cold sores’ on lips (~90% of population) Type 2 - sexually transmitted disease that causes "cold sores" on the genitals (~ 25% of US adults). Human Herpes Virus 8 (HHV8) a.k.a Kaposi’s sarcoma associated virus HHV8 endemic regions Kaposi’s sarcoma HHV8 and transformation EBV- Epstein Barr Virus most potent transforming agent, widespread in all human populations usually carried as an asymptomatic persistent infection. virus sometimes associated with the pathogenesis of certain types of lymphoid and epithelial cancers, including Burkitt lymphoma (BL), Hodgkin disease and nasopharyngeal carcinoma (NPC). EBV associated cancers Burkitt’s lymphoma Nasopharyngeal carcinoma NPC tissue stained for the presence of EBV late antigens. Hodgkin’s lymphoma 40-50% of patients are EBV seropositive in vivo interactions between EBV and host cells EBV infection and Burkitt’s lymphoma Trends in Molecular Medicine Volume 10, Issue 7 , 1 July 2004, Pages 331-336 Nasopharyngeal carcinoma (NPC) EBV and pathogenesis of NPC Summary of EBV aetiology of several different lymphoid and epithelial malignancies. EBV-encoded latent genes induce B-cell transformation in vitro by altering cellular gene transcription and constitutively activating key cell-signalling pathways. EBV exploits the physiology of normal B-cell differentiation to persist within the memory-Bcell pool of the immunocompetent host. Putative life cycle of HBV Human papilloma virus (HPV) 90% of cervical cancers contain HPV DNA. 4 types (HPV-16, HPV-18, HPV-31, and HPV-45) accounted for about 80% of the HPV-positive cancers. HPV-16 most common type of HPV found in cervical cancers. HPV-16 is the most common type in squamous cell cancers. HPV-18 is the predominant type in adenocarcinomas, Copyright © 1998 - 2000 David Reznik, D.D.S. All Rights Reserved Regions of stratified epithelium where HPV is maintained and amplified Cancer transformation Transforming activity of HPV16 is associated with mainly E6 and E7proteins E6 and E7 are multifunctional proteins that can increase cell proliferation and survival by interfering with tumour suppressor activity. Cancer transformation RNA viruses • Unstable RNA genome • prone to mutations • Generates genetic diversity and escape antiviral therapy • Can be oncogenic (e.g.hepatitis C virus HCV) hepatitis C virus HCV Affects 3% of global population Infects primarily hepatocytes 50-80% of infected individuals go on to develop hepatocellular carcinoma (HCC) At least 6 genotypes known HCV life cycle What causes hepatocellular carcinoma? • Current hypothesis is HBV and HCV infection • HBV integrate into genome and a protein Hbx is known to cause HCC • HCV does not integrate into the genome but can interact with host proteins and cause an inflammatory response, which can transform cells e.g. HCV proteins NS3 and NS5A can disrupt transcription factors leading to proliferation and inhibition of apoptosis Human Immunodeficiency Virus HIV HIV life cycle See animation at http://www.roche-hiv.com/home/home.cfm HIV genome 3 structural genes gag (group specific antigen) encodes matrix, capsid, nucleocapsid proteins pol (polymerase) encodes reverse transcriptase, integrase, protease env (envelope) encodes surface & transmembrane proteins 6 regulatory genes rev (regulatory virus protein) tat (transactivator) nef (negative regulatory factor) vif, vpr, vpu, env (envelope) encodes surface & transmembrane protein Course of HIV infection Antiretroviral or anti HIV therapy All approved anti-HIV drugs attempt to block viral replication within cells by inhibiting either RT or HIV protease. • Nucleoside analogues mimic HIV nucleosides preventing DNA strand completion e.g. Zidovudine (AZT), ddI, ddC, Stavudine • Non nucleoside RT inhibitors (NNRTI) e.g Delavirdine and Nevirapine • Protease inhibitors block active, catalytic site of HIV protease Multidrug therapy • HAART (highly active antiretroviral therapy) usually consists of triple therapy including – 2 nucleoside analogues + 1 protease inhibitor – 1 non nucleoside RT inhibitor + 1(2) prot. inhibitor EBV genome EBV-encoded nuclear antigen 2 (EBNA2) latent membrane protein 1 LMP2