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Tumor Viruses

For most viruses: Genome viral proteins. Replication Lysis Progeny virions . Tumor Viruses. Life Cycles. Lytic Life Cycle Virus Infection Cell Replication Lysis Progeny. Budding Life Cycle Virus Infection Cell Replication Virus

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Tumor Viruses

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  1. For most viruses: Genome viral proteins Replication Lysis Progeny virions Tumor Viruses

  2. Life Cycles Lytic Life Cycle Virus Infection Cell Replication Lysis Progeny

  3. Budding Life Cycle Virus Infection Cell Replication Virus Integration of viral chromosome into the host cell DNA may occur Life Cycles

  4. Latent Life Cycle Virus Cell Integration (usually) Transformation Virus-specific proteins expressed - No mature virus Changes in the properties of host cell Tumor Viruses

  5. Tumor Viruses Transformation: Loss of growth control Ability to form tumors - viral genes interfere with control of cell replication DNA may be: Integrated - replicates with DNA - provirus Independent - plasmid

  6. Tumor Viruses • Lecture Outline – We shall see that: • Two basic classes of tumor viruses • DNA tumor viruses • RNA tumor viruses (RETROVIRUSES) • These form tumors • Virus genome may integrate • Virus genes are expressed • Viruses often have oncogenes that transform the cell

  7. Tumor Viruses • Lecture Outline 2 • Oncogenes are not unique to tumor viruses • Cells have homologous genes • Proto-oncogenes • Transforming virus may carry its own oncogene or activate a cellular proto-oncogene • Factors other than viruses can activate a cellular oncogene so that cell is transformed • Cellular oncogenes have growth control and differentiation functions • Cells also have anti-oncogenes that suppress transformation

  8. Two Major Classes of Tumor Viruses DNA Tumor Viruses DNA viral genome DNA-dependentDNA polymerase(Host or viral) Host RNA polymerase Viral mRNA Viral protein

  9. RNA Tumor Viruses Viral RNA genome Reverse transcriptase (Virus-encoded) Viral DNA genome (integrated) DNA-dependent RNA polymerase (Host RNA pol II) Viral genomic RNA Splicing (Host splicing enzymes) messenger RNA viral protein Virus Important: Use HOSTRNA polymerase to make its genome An enzyme that normallymakes mRNA

  10. TRANSFORMATION Both DNA and RNA tumor viruses can transform cells Integration occurs (usually) Similar mechanisms VIRAL TRANSFORMATION The changes in the biological functions of a cell that result from REGULATION of the cell’s metabolism by viral genes and that confer on the infected cell certain properties characteristic of NEOPLASIA These changes often result from the integration of the viral genome into the host cell DNA

  11. TRANSFORMATION • Among the many altered properties of the TRANSFORMED CELL are: • Loss of growth control (loss of contact inhibition in cultured cells) • Tumor formation • Mobility • Reduced adhesion • Transformed cells frequently exhibit chromosomal aberrations

  12. DNA Tumor Viruses DNA genome mRNA protein virus Host RNA polymerase II Host enzymes OR TRANSFORMATIONIn transformation usually only EARLY functions are expressed

  13. DNA Tumor Viruses In Human Cancer • Papilloma Viruses • cause natural cancers in animals • cause benign warts • ubiquitous • epitheliotropic - most human are malignancies of epithelial cells

  14. Papilloma Viruses • epidermodysplasia verruciformis • wart malignant squamous cell carcinoma DNA Tumor Viruses In Human Cancer

  15. DNA Tumor Viruses In Human Cancer Epidermodysplasia verruciformis Papilloma virus

  16. 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 Squamous cell carcinoma: Larynx Esophagus All histologically similar Lung 10% of human cancers may be HPV-linked

  17. Papilloma Viruses • 51 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) • German study: 1 in 30 HPV-16 positive women cervical cancer • BUT a minority of HPV 16 and 18 positive people get neoplasia • Possibility of cofactors (which have been identified in bovine alimentary tract carcinomas) DNA Tumor Viruses In Human Cancer EPIDEMIOLOGIAL STUDIES BUT: HPV 16 and HPV 18 do transform human keratinocytes

  18. DNA Tumor Viruses In Human Cancer • Polyoma Viruses • Simian virus 40 - juvenile hamster sarcomas, transformation • Polyoma - mouse leukemia, in vitro transformation • Human polyomas (JC and BK) - monkey sarcoma, transformation • No polyoma virus has been shown to cause transformation in its natural host species • PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY • Polyoma virus transforms cells when the genome is incomplete • Viral DNA is linearized and integrated at many sites

  19. DNA Tumor Viruses In Human Cancer ASSOCIATION OF JC WITH PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY • 70-80% of the population: JC seropositive • Causes progressive multifocal leukoencephalopathy • Disease associated with immunosuppression. • 1979: the rate of occurrence - 1.5 per 10 million population. • Much more common because of AIDS • Seen in 5% of AIDS patients

  20. Polyoma Viruses • Only tumor antigens are transcribed by host enzyme (RNA pol II) • “Early functions” • control DNA synthesis in infected cell • Early functions Tumor antigens ONCOGENES DNA Tumor Viruses In Human Cancer • Deletions in early functions result in • No viral replication • No transformation • Early functions needed for both lytic infection and transformation

  21. DNA Tumor Viruses In Human Cancer ONCOGENE A gene that codes for a protein that potentially can transform a normal cell into a malignant cell An oncogene may be transmitted by a virus in which case it is known as a VIRAL ONCOGENE v-onc

  22. DNA Tumor Viruses In Human Cancer SV 40 Oncogenes Large T antigen Small T antigenLarge T is found in nucleus and at the cell surface Polyoma Oncogenes Large T Middle T Small T

  23. DNA Tumor Viruses In Human Cancer In Polyoma Viruses: T antigens = Oncogenes T antigens are true viral genes They are necessary for: Lytic Infection Transformation

  24. DNA Tumor Viruses In Human Cancer Adenoviruses Highly oncogenic in animals Only part of virus integrated Always the same part Early functions E1A region: 2 T antigens E1B region: 1 T antigen E1A and E1B = Oncogenes

  25. DNA Tumor Viruses In Human Cancer • Herpes Viruses • Considerable evidence for role in human cancer • Some very tumorigenic in animals • Viral DNA found in small proportion of tumor cells: “hit and run” • Epstein-Barr Virus • Burkitt’s Lymphoma • Nasopharyngeal cancer • Infectious mononucleosis • Transforms human B-lymphocytes in vitro

  26. DNA Tumor Viruses In Human Cancer Herpes Viruses continued • Human cytomegalovirus • Human herpes virus 8 (Kaposi sarcoma-associated virus) • Herpes simplex 2 (cervical carcinoma?) Herpes virus DNA is found in only a small number of herpes-transformed cells Complex mode of transformation

  27. Hepatitis B Virus DNA genome RNA polymerase II RNA Provirus Reverse transcriptase DNA genome DNA Tumor Viruses In Human Cancer

  28. DNA Tumor Viruses In Human CancerHepatitis B continued • Vast public health problem • 10% of population in underdeveloped countries are chronic carriers • Long latency

  29. DNA Tumor Viruses In Human CancerHepatitis B continued Epidemiology: Strong correlation between HBV and hepatocellular carcinoma China: 500,000 - 1 million new cases of hepatocellular carcinoma per year Taiwan: Relative risk of getting HCC is 217 x risk of non-carriers 51% of deaths of HB S antigen carriers are from HCC or liver disease 2% of non- HB S positives

  30. DNA Tumor Viruses In Human Cancer Summary • Can transform cells or have lytic life cycle • Often integrate into host genome • In transformation ONLY early genes are transcribed

  31. = early functions • necessary for transformation or lysis • No similar gene in host genome • T antigen = ONCOGENE important important important DNA Tumor Viruses In Human Cancer Summary T ANTIGENS

  32. virus virus RNA Tumor Viruses RNA Genome - Retroviruses RNA-dependent DNA Polymerase encoded by virus REVERSE TRANSCRIPTASE RNA genome Reverse transcriptase DNA genome Integrase Integrates Host RNA polymerase II RNA genome host

  33. RNA Tumor Viruses Retroviruses known to cause human cancer • Human T cell lymphotropic virus -1 (HTLV-1) • Adult T cell leukemia, Sezary T-cell leukemia • Africa, Caribbean, Some Japanese Islands • Human T cell lymphotropic virus -2 (HTLV-2) • Hairy cell leukemia • HIV?

  34. RNA Tumor Viruses

  35. RNA Tumor Viruses A normal retrovirus has: 3 genes GAG : internal proteins ENV: Envelope glycoproteins POL: Enzymes Reverse transcriptase Integrase Protease

  36. RNA Tumor Viruses • RNA is: • Diploid Capped and polyadenylated • Positive sense (same as mRNA) Viral RNA cannot be read as mRNA New mRNA must be made Virus must make negative sense DNA before proteins are made Therefore virus must carry REVERSE TRANSCRIPTASE into the cell

  37. RNA Tumor Viruses

  38. RNA Tumor Viruses • Groups of Retroviruses • Oncovirinae • Tumor viruses and similar • Lentiviruses • Long latent period • Progressive chronic disease • Visna HIV • Spumavirinae important important

  39. Retrovirus Life Cycle Endocytosis Fusion of membranes Release of nucleocapsid to cytoplasm Nucleus RNA Tumor Viruses

  40. RNA Tumor Viruses • Parental RNA • RNA/DNA Hybrid • Linear DNA/DNA duplex • Circular Duplex DNA • Integration Replication (DNA genome in cell) • Transcription Viral RNA genome mRNA protein Reverse transcriptase Reverse transcriptase Integrase Host DNA polymerase Host splicing enzymes Host RNA pol II

  41. RNA Tumor Viruses Drawback to this lifestyle Genomic RNA Reverse transcriptase DNA Host RNA pol II Genomic RNA Pol II is a host enzyme that, in the uninfected cell, makes mRNA When making mRNA, pol II does not copy entire gene to RNA

  42. Problem of using RNA pol II to copy a gene RNA synthesis initiation site promotor RNA pol II RNA synthesis termination site Viral genomicRNA RT primer Reverse transcriptase dsDNA Result: New copy of viral RNA is shorter - lacks control sequences

  43. RNA Tumor Viruses RNA polymerase II will not copy • Upstream sequences from transcription initiation site • Promotors / Enhancers • Down stream sequences from transcription termination site • Enhancers / Poly A site / termination site ? Perhaps virus could integrate downstream of a promotor etc so that the cell provides sequences OR Virus provides its own promotors etc BUT not copied!

  44. Repeatregion Repeatregion DNA U3 R U5 GAG POL ENV U3 R U5 LTR RNA Tumor Viruses Clue: Difference in the two forms RNA R U5 GAG POL ENV U3 R

  45. POLII RNA termination site RNA initiation site R U5 Viral RNA U3 R Reverse transcriptase U3 R U5 U3 R U5 Long terminal repeats are formed POLII

  46. Long Terminal Repeat Formation movie

  47. POLII RNA termination site RNA initiation site Retroviruses can have only one promotor LTR LTR POLII Therefore only one long RNA can be made Therefore mRNA requires processing Explains why RNA has to be positive sense U5

  48. Rous Sarcoma Virus R U5 GAG POL ENV U3 R Some retroviruses have an extra gene “typical retrovirus” R U5 GAG POL ENV U3 R SRC

  49. Some retroviruses have an oncogene instead of their regular genes Avian Myeloblastosis Virus R U5 GAG POL MYB U3 R Feline Sarcoma Virus (FSV) R U5 dGAG FMS dENV U3 R Avian Myelocytoma Virus (MC29) R U5 dGAG MYC dENV U3 R

  50. RNA Tumor Viruses Viral Oncogene V-onc Cellular Proto-oncogene C-onc

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