Presentation on theme: "Oncogenic viruses Key Concepts Normal cells infected with certain viruses can be transformed into cancer cells due to expression or activation of viral."— Presentation transcript:
Oncogenic viruses Key Concepts Normal cells infected with certain viruses can be transformed into cancer cells due to expression or activation of viral oncogenes Transformation can result in integration of viral genes or genomes into the host genome
Approximately one in six human cancers is caused by a human tumour virus!! Herpesviridae Human Herpes Virus 8 ( HHV8) a.k.a Kaposis sarcoma associated virus Epstein-Barr virus (EBV) Papovaviridae human papilloma virus (HPV) Hepadnaviridae hepatitis B virus-(HBV) Flaviviridae (hepatitis C virus HCV) Retroviridae Human T-cell lymphotropic virus (HTLV type I) DNA viruses RNA viruses
Overview of viral replication
Genome replication DNA virusesRNA viruses
How does tumourigenicity occur? Viral genomes show the presence of several human gene homologues (cellular proto-oncogenes) Infective viruses kidnap proto-oncogenes which are then transformed into oncogenes e.g. c-src/v-src ; v-myc/c-myc ; vIL6/ IL6 (interleukin 6)
Herpesviridae Human Herpes Virus 8 ( HHV8) a.k.a Kaposis sarcoma associated virus Epstein-Barr virus (EBV) DNA viruses
EBV- Epstein Barr Virus most potent transforming agent, widespread in all human populations usually carried as an asymptomatic persistent infection (latent). virus sometimes associated with the pathogenesis of certain types of lymphoid and epithelial cancers, including Burkitt lymphoma (BL), Hodgkin disease and nasopharyngeal carcinoma (NPC).
Burkitts lymphoma Nasopharyngeal carcinoma Hodgkins lymphoma 40-50% of patients are EBV seropositive NPC tissue stained for the presence of EBV late antigens.
EBV genome and host cell transformation EBV-encoded nuclear antigen 2 (EBNA2) latent membrane protein 1 (LMP1) mimics CD40 receptor LMP2 mimics the B cell receptor
in vivo interactions between EBV and host cells
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-B- cell pool of the immunocompetent host. Summary of EBV
HPV life cycle Infection established in basal epithelial layers where viral genome maintained as an episome Viral replication occurs in suprabasal layers Infections are therefore long lasting
Integration into the host genome
HPV 16 produces only eight proteins E1Replication of viral DNA; maintenance of viral episome; essential for viral replication and control of gene transcription E2Essential for viral replication; repression of E6 and E7 E4Forms filamentous cytoplasmic networks E5Prevents acidification of endosomes; interaction with Epidermal Growth Factor (EGF) /Platelet-Derived Growth Factor (PDGF) LCROrigin of DNA replication; regulation of HPV gene expression ProteinFunction L1Major capsid protein in the virus particle; by itself, L1 can assemble into capsomers and then form virus-like particles (VLPs) L2Minor capsid protein in the virus particle; L2 binds to DNA E6Destruction of p53 tumor suppressor protein E7Inactivation of Retinoblastoma tumor suppressor protein (Rb)
Development of cancer
E6 and E7 proteins inactivate tumour suppressor proteins p53 and pRB 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.
References Chapter 3: Biology of Cancer by RA Weinberg Optional reading Oncogenic viruses by Dennis J McCance Epstein-Barr virus: 40 years on Nature Rev Cancer 4 (10) Oct 2004 Young LS, Rickinson AB How will HPV vaccines affect cervical cancer? Roden R, Wu TC Nat Rev Cancer Oct;6(10):753-63
The following slides are for general interest only (since there is not enough time to cover all viruses in detail) Translated as THERE WILL BE NO SPECIFIC QUESTION ON RETROVIRUSES IN THE EXAM
RNA viruses Unstable RNA genome prone to mutations Generates genetic diversity and escape antiviral therapy Can be oncogenic (e.g.hepatitis C virus HCV)
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
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
What causes hepatocellular carcinoma? HBV and HCV co-infection? HBV integrates into genome and produces a protein Hbx, involved in 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
HCV life cycle
Human Herpes Virus 8 (HHV8) or Kaposis 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 Kaposis sarcoma associated virus HHV8 endemic regions
HHV8 and transformation Most people infected with HHV8 do not get KS Immunosuppressed individuals are susceptible Viral homologues of several human proteins (e.g. v-cyc, vIL6)