Presentation is loading. Please wait.

Presentation is loading. Please wait.

Oncogenic viruses Key Concepts Normal cells infected with certain viruses can be transformed into cancer cells due to expression or activation of viral.

Similar presentations


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:

1 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

2 Figure 3.1; 3.2 The Biology of Cancer (© Garland Science 2007) 1909, Peyton Rous discovers sarcoma-inducing agent in chickens Is cancer infectious?

3 Figure 3.7a The Biology of Cancer (© Garland Science 2007) Normal cells infected with certain viruses can be transformed

4 Table 3.2 The Biology of Cancer (© Garland Science 2007) Viral transformation can induce cellular changes including tumourigenicity

5 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

6 Overview of viral replication

7 Genome replication DNA virusesRNA viruses

8 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)

9 Figure 3.23a The Biology of Cancer (© Garland Science 2007) Insertion of viral sequences into host DNA carrying the proto-oncogene E.g. Insertion of ALV into c-myc protooncogene

10 v-myc and c-myc (myc oncogene)

11 Table 3.4 The Biology of Cancer (© Garland Science 2007)

12 Herpesviridae Human Herpes Virus 8 ( HHV8) a.k.a Kaposis sarcoma associated virus Epstein-Barr virus (EBV) DNA viruses

13 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).

14 Burkitts lymphoma Nasopharyngeal carcinoma Hodgkins lymphoma 40-50% of patients are EBV seropositive NPC tissue stained for the presence of EBV late antigens.

15 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

16 in vivo interactions between EBV and host cells

17 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

18 Human papilloma virus (HPV) 90% of cervical cancers contain HPV DNA. 4 types (HPV-16, HPV-18, HPV-31, and HPV-45) accounts for ~ 80% of HPV-positive cancers. 4 types (HPV-16, HPV-18, HPV-31, and HPV-45) accounts for ~ 80% of HPV-positive cancers. HPV-16 & 18 most common type of HPV found in ~70% of cervical carcinomas. HPV-6,11 : common in genital warts Copyright © 1998 - 2000 David Reznik, D.D.S. All Rights Reserved

19 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

20 Integration into the host genome

21 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)

22 Development of cancer

23 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.

24 Inactivation of pRB by E7

25 To prevent cervical cancers in children aged 9–15 years and women from 16-26 years expected to prevent up to 70% of nearly 100 percent effective in preventing precancerous cervical lesions, precancerous vaginal and vulvar lesions and genital warts caused by infection with the HPV types 6, 11, 16 or 18 in women between the ages of 16 and 26. Gardasil © (Merck): quadrivalent recombinant vaccine against HPV types 6, 11, 16 and 18

26 References Chapter 3: Biology of Cancer by RA Weinberg Optional reading Oncogenic viruses by Dennis J McCance www.els.net www.els.net Epstein-Barr virus: 40 years on Nature Rev Cancer 4 (10)757-68 Oct 2004 Young LS, Rickinson AB How will HPV vaccines affect cervical cancer? Roden R, Wu TC Nat Rev Cancer. 2006 Oct;6(10):753-63

27 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

28 RNA viruses Unstable RNA genome prone to mutations Generates genetic diversity and escape antiviral therapy Can be oncogenic (e.g.hepatitis C virus HCV)

29 Figure 3.17 The Biology of Cancer (© Garland Science 2007) Retroviral replication

30 Human Immunodeficiency Virus HIV

31 HIV life cycle See animation at http://www.roche-hiv.com/home/home.cfm

32 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

33 Course of HIV infection

34 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

35 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

36 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

37 HCV life cycle

38 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).

39 Human Herpes Virus 8 ( HHV8) a.k.a Kaposis sarcoma associated virus HHV8 endemic regions

40 Kaposis sarcoma

41 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)


Download ppt "Oncogenic viruses Key Concepts Normal cells infected with certain viruses can be transformed into cancer cells due to expression or activation of viral."

Similar presentations


Ads by Google