1 / 43

Paper Discussion

Paper Discussion. Adeno-Associated Virus Type 2 Induced Apoptosis in Human Papillomavirus-Infected Cell Lines but Not in Normal Keratinocytes. Alam, S, and Meyers, C. 2009 J. Virol. 83:10286-10292. Viruses cause cancer. Why has the study of viruses and cancer been important?

fran
Télécharger la présentation

Paper Discussion

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

  1. Paper Discussion Adeno-Associated Virus Type 2 Induced Apoptosis in Human Papillomavirus-Infected Cell Lines but Not in Normal Keratinocytes. Alam, S, and Meyers, C. 2009 J. Virol. 83:10286-10292

  2. Viruses cause cancer Why has the study of viruses and cancer been important? - We learn about the basic mechanisms of specific types of tumors. - We identify fundamental pathways important for oncogenesis - viruses are lower complexity - We can identify potential unique therapeutic targets for viral associated tumors

  3. Viruses cause cancer • 20-30% of cancers are known to have viral etiology • But as more research is done, • this percentage is likely to be found to be higher

  4. Major human Oncogenic Viruses DNA Viruses Small DNA tumor viruses - Adenovirus - SV40 - Human Papilloma virus (HPV) Herpesviruses (large) - Epstein Barr virus (EBV) - Kaposi’s Sarcoma Herpesvirus (KSHV) Other - Hepatitis virus B RNA viruses Human T-cell Leukemia Virus 1 (HTLV1) XMRV (Xenotropic Murine Leukemia Virus) Hepatitis virus C

  5. Changes in cell that are at the roots of cancer • Genetic and epigenetic alterations: • Mutations • Deletions • Recombinations • Transpositions • Epigenetic alterations (DNA methylation, imprinting) • Acquisition of viral genetic material • Various combinations of these lead to the development of cancers - some viruses contribute single hits while others contribute multiple hits.

  6. Source of genetic alterations • Inherited • Somatic • Random • Replication errors • DNA repair errors • Transposition (e.g. retrotransposons) • Exposure to deleterious environmental agents • Radiation • carcinogenic chemicals • Viruses • Other persistent infections

  7. How do Viruses contribute to cancer? • Integrations that cause activation or inactivation of oncogenes or tumor suppressors (e.g. RNA viruses) • Expression of genes that alter key signal transduction pathways - this is our focus • Chronic activation of inflammatory responses

  8. Why do viruses cause cancer? • Viruses and cancer cells have similar needs • Proliferation control • Cell death control • Modulation of immune response • Induction of vascularization • Metastasis (tumor)/cell migration (viruses)

  9. If you’re infected, does this mean that you will get cancer? • No • Viruses did not specifically evolve with the need to cause cancer - they simply have similar (but distinct) needs • Development of tumors almost always requires: • Additional genetic alterations and/or • Compromised host (e.g. immuno-suppression)

  10. Major human Oncogenic Viruses DNA Viruses Small DNA tumor viruses - Adenovirus - SV40 - Human Papilloma virus (HPV) Herpesviruses (large) - Epstein Barr virus (EBV) - Kaposi’s Sarcoma Herpesvirus (KSHV) Other - Hepatitis virus B RNA viruses Human T-cell Leukemia Virus 1 (HTLV1) XMRV (Xenotropic Murine Leukemia Virus) Hepatitis virus C

  11. Small DNA tumor viruses • Adenovirus • Human virus but only causes cancer in non-human cells • SV40 • Mesothelioma • HPV • Cervical Cancer • Squamous cell anal carcinoma • Penile cancer • Oral cancers

  12. Small DNA tumor viruses • HPV • SV40 • Adenovirus • Normally replicate episomally but almost always found integrated in associated tumors - why? • Replication must be abortive • HPV, viral encoded negative regulatory factor must be deleted

  13. Papilloma Viruses urogenital cancer wart malignant squamous cell carcinoma Papilloma viruses are found in 91% of women with cervical cancer DNA Tumor Viruses In Human Cancer 10% of human cancers may be HPV-linked 16% of all female cancers linked to HPV

  14. DNA Tumor Viruses In Human Cancer • Papilloma Viruses • >100 types identified - most common are types 6 and 11 • Most cervical, vulvar and penile cancers are ASSOCIATED with types 16 and 18 (70% of penile cancers) Effective Vaccine (quadrivalent recombinant HPV 6, 11, 16 and 18 proteins made in yeast - Gardasil)

  15. Papilloma Viruses • The important transforming genes in papilloma viruses are the non-structural regulatory genes, E6 and E7 • HPV is normally episomal but is always integrated in tumors

  16. Adenoviruses Highly oncogenic in animals Only part of virus integrated Always the same part Early (regulatory) genes E1A and E1B = Oncogenes

  17. SV40 • The important transforming gene is T Ag - provides similar functions as E1A + E1B (Adenovirus) and E6 and E7 (HPV)

  18. Abortive replication is key to oncogenesis by these small viruses • Expression of early (regulatory) genes in absence of structural genes and virus production • Can occur by infection of non-permissive host • Can occur by integrations that delete regions of viral genome required for replication but leave early genes intact.

  19. Small DNA Tumor Viruses • What are the needs of small DNA tumor viruses that make them oncogenic and • What are the key mechanisms through which they attain their needs?

  20. Small DNA Tumor Viruses DNA viral genome Utilizes Host Cell DNA Replication Machinery Host RNA polymerase Viral mRNA Viral protein Need cells that are in S-phase to replicate viral genome Host enzymes

  21. Inappropriate activation of cell cycle • Apoptosis • e.g. • Overexpression of E2F1 or c-Myc induces cell cycle and apoptosis • Defense mechanism against rogue proliferating cells? • - Same is true for over-expression of Adenovirus E1A or HPV E7

  22. Encode early genes that inhibit apoptosis Adenovirus E1B HPV E6 SV40 T Ag

  23. SV40 and HPV

  24. Adenovirus E1B is Bcl2 family member - blocks function of pro-apoptotic Bcl2 family members through dimerization

  25. Summary Small DNA tumor viruses usually replicate in episomal form but are found integrated in viral associated tumors Early genes promote cell cycle progression and prevent apoptosis Adenovirus - E1A (cell cycle) and E1B (apoptosis) HPV - E7 (cell cycle) and E6 (apoptosis) SV40 - T Ag (cell cycle and apoptosis)

  26. Herpes viruses • Oncogenic members: • Epstein Barr virus (EBV) • Kaposi’s Sarcoma Herpes virus (KSHV) • Oncogenic mechanisms are distinct from small • DNA tumor viruses • - Don’t need to integrate • - Cell cycle is not driven by lytic replication regulatory genes

  27. Herpes viruses Hallmark of herpesviruses: Existence of latent stage (in addition to lytic/replicative stage)

  28. Herpes viruses Lytic replication phase for herpesviruses: - Herpesviruses are large and encode 80-100 lytic associated genes - Encode their own DNA polymerase and replication accessory enzymes - Therefore, they don’t require an S-phase environment for replication - Encode early genes that induce cell cycle arrest

  29. Herpes viruses Latency: - Small subset of viral genes are expressed that are not expressed during lytic replication. - Latency is partly a way for virus to hide from immune system - In cases of EBV and KSHV, latency genes can also induce cell differentiation/activation programs that facilitate expansion of infected cell population and induce trafficking to specific lymphoid compartments that are suited to the life cycle of the virus

  30. Herpes viruses • Human Herpesviruses and latency function: • Epstein Barr virus (EBV) - multiple functions • Kaposi’s Sarcoma Herpes virus (KSHV) - multiple functions • Cytomegalovirus (CMV) - Stealth mechanism • Herpes Simplex (HSV) - Stealth mechanism

  31. Epstein Barr virus • Pathologies in immuno-competent individuals • Infectious mononucleosis • Burkitt’s Lymphoma • Hodgkin’s lymphoma • Nasopharyngeal carcinoma • Pathologies in immuno-compromised individuals • Post-transplant lymphoproliferative diseases (PTLD) • Hodgkin’s lymphoma • A variety of non-Hodgkin’s lymphoblastoid malignancies

  32. Epstein Barr virus • Latency genes • Non-antigenic • EBNA1 (Epstein Barr Nuclear Antigen 1) - episomal replication and segregation function • Antigenic • EBNA2 • EBNA3A, 3B, 3C • EBNA-LP • LMP1 (Latent Membrane Protein 1) • LMP2A Those in Red are key regulatory genes involved in B cell activation

  33. Epstein Barr virus 4 different types of latency True Latency - no viral gene expression EBNA1 only - EBNA1 (non-antigenic) Default - EBNA1, LMP1, and LMP2 (moderately antigenic) Growth - EBNA1, LMP1, LMP2, EBNA2, EBNA-LP, EBNA3A, 3B, 3C (highly antigenic) • Growth program • Initial infection (prior to immune response) • Immuno-compromised individuals • - in vitro infection of naïve peripheral blood lymhocytes

  34. Epstein Barr virus • Greater than 90% of US population are carriers of EBV • Only small percentage of carriers develop tumors - who? • Immuno-compromised - allows full set of oncongenic genes to be expressed • Immuno-competent who have multiple additional genetic hits EBV does not integrate - exists as an extrachromosomal episome

  35. Kaposi’s sarcoma Kaposi’s Sarcoma Herpes Virus - HHV-8 • Hematologic malignancies • Primary effusion lymphoma • Multicentric Castleman's disease (MCD) – a rare lymphoproliferative disorder (AIDS) • MCD-related immunoblastic/plasmablastic lymphoma • Various atypical lymphoproliferative disorders

  36. Hepatitis B and C Long latency period to development of HCC (Hepatocellular Carcinoma) 20-30 years Mechanism is probably due to chronic inflammatory response

  37. Silver lining to viral associate cancers Offer unique targets not common to normal uninfected cells • Examples: • HPV • Gardasil • EBV • In vitro production of EBV specific CTLs for PTLD • Treatment with agents that induce lytic cycle • (butyrate plus Gancyclovir) • KSHV • - Anti-retroviral therapy

More Related