Uploaded byDr. Rakesh Prasad Sah
Oncogenic Viruses
Oncogenic viruses are viruses that can cause cancer. They do so by inserting their DNA into host cells and altering gene expression in ways that promote uncontrolled cell growth and division. Some key points: - Viruses like HPV, EBV, HBV can lay dormant in the body for years before causing tumors by disrupting tumor suppressor genes or activating oncogenes. - Oncogenic viruses establish persistent infections to evade the immune system and immunosuppression increases cancer risk. - Viral oncogenes are incorporated into host cell DNA and cause overexpression of cellular genes involved in growth regulation. - Cancers linked to oncogenic viruses include cervical cancer from HPV, lymphomas
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Oncogenic Viruses
- 1. By Dr. RakeshPrasad Sah Assistant Professor, Microbiology Oncogenic Viruses
- 2. Introduction • Viruses thatproduce tumors in hosts/experimental animals or induce malignant transformation of cells in culture are called Oncogenic viruses.
- 3. Features of ViralOncogenesis • Causes cancer in humans & animals • long latency between viral infection and tumorigenesis • modulate growth control pathways in cells • viral markers are present in tumor cells
- 4. Genes Regulating HostCell Growth • Four categories of genes present in host which regulate the cellular growth and proliferation. • Defect in any of these regulatory genes lead to transformation of the normal cells abnormal tumor cells. • Proto-oncogenes – Promote host cells growth & proliferation – Essential for life – Over activation of protooncogene transformation of host cells
- 5. • Anti-oncogenes ortumor suppressor genes – Continuously check cellular growth and proliferation and supress any abnormal proliferation of cells. – Inactivation of tumor suppressor genes permits the abnormal event to occur resulting in cell transformation. • DNA repair genes: – Normal host genes that repair any mutations occurring during the cell growth. – Failure of DNA repair genes lead to inability to repair the damaged DNA and may lead to persistent mutation. Genes Regulating Host Cell Growth
- 6. • Apoptosis-regulatory genes: –Control the programmed cell death – Either up-regulate or down-regulate apoptosis depending on the requirement. – May act as proto-oncogenes or tumor suppressor genes. – Mutations in apoptosis-regulatory genes are another mechanism by which the cellular transformation is accelerated. Genes Regulating Host Cell Growth
- 8. • Oncogenesis -Anabnormal growth of tissue resulting from uncontrolled, progressive multiplication of cells and serving no physiological function. Result of genetic changes that alter the expression or function of proteins that play critical roles in the control of cell growth and division. • Proto-oncogenes - normal (pre-mutation) (pre-diseased) genes – present in normal cells – conserved in their genomes – code for proteins which regulate cell growth & differentiation • Oncogenes – mutated versions of proto-oncogenes – contribute to cancer development by disrupting a cell's ability to control its own growth.
- 9. C-onc (Cellular Oncogenes) •Cellular counter part of viral oncogenes present in cancer cells • Encodes proteins triggering transformation of normal cells V-onc (Viral Oncogenes) •Present in viruses •Essential for replication of virus. •Also called ‘cancer genes’ •Encodes proteins triggering transformation of normal cells into cancer cells
- 11. TRANSFORMATION • alteration ina cell’s properties that leads to immortalization and different growth patterns that result from alteration in cell cycle. • Acute transforming viruses – Retrovirus (alpha, gamma) – Replication defective (does not produce viral infection) – Contain viral oncogene ( transform cells in culture ) • Non acute transforming viruses – retrovirus (alpha,beta,gamma) – replication competent (cause viral disease) – lack viral oncogene (high level of infection months before tumor )
- 12. Events that mustoccur before oncogenesis • Establishing persistent infection • Evades host immune response • Immunosuppression • Host cell susceptibility • Retention of viral nucleic acid inside the host cells
- 13. Establishing persistent infection •Prolonged interaction between the tumor virus and the host cell is essential for oncogenesis to develop • Possible only when the tumor virus establishes a longterm persistent infection in host cells.
- 14. Evades host immuneresponse • Host immune response plays an important role in viral clearance. • Tumor virus follows various evasion mechanisms to bypass the host immune response, which are as follow – By restricting the expression of viral genes which go unnoticed by the immune cells (e.g. EBV in B cells) – Infecting the sites that are relatively inaccessible to immune responses (HPV infecting epidermis) – Undergoing mutation of certain genes that allows the virus to escape from the host cellular and humoral responses (HIV). – Infection and suppression of essential immune cells (CD4 T cell by HIV).
- 15. Immunosuppression • Host allowsthe cancer cells to proliferate and escape the host immune response • Immunosuppressed organ transplant recipients and HIVinfected individuals are at increased risk of EBV and HPV associated malignancies.
- 16. Host cell susceptibility •Host cells may be permissive or non-permissive for replication of a given virus. – Permissive cells support viral growth and replication of a progeny virus; non- permissive cells do not. – Non-permissive cells - host cells that either do not have surface receptors for viral attachment or do not support the viral replication or the release of virus progeny. • Risk of oncogenicity is more when a non-permissive cell is infected by a tumor virus.
- 18. Retention of viralnucleic acid inside the host cells • Essential to maintain a stable genetic change that occurs in a tumor cell. • DNA copies of tumor viruses (both DNA & RNA tumor viruses) are integrated within the host cell chromosome. • RNA of retroviruses get reverse transcribed to DNA • Hepatitis C virus is an exception, its RNA is neither reverse transcribed, nor integrated into the host chromosome; but are maintained in the tumor cells.
- 19. Viruses Genetic factorsof host irrespective of viral infection Changes in genome of somatic cells Activation of growth promoting oncogenes Inactivation of cancer suppressor genes Expression of altered gene products and loss of regulatory gene products Neoplasm Mechanism of Neoplasm Development
- 20. Direct Acting IndirectActing Loss of normal growth regulation processes, Affection of DNA repair mechanisms Genetic instability Mutagenic phenotype Acute transforming viruses possess V–onc into the host cell chromosomes. Oncogenic viruses possess “Transforming gene” insert into host DNA altered expression of Pre-existing cellular gene which regulate cell growth (P.T.A.D.) Mechanism of Oncogenecity P Protooncogene T Tumor suppressor gene A Apoptosis regulatory genes D DNA repair genes
- 21. Normal C-myc Acute TransformingVirus Capture Mutation Slow transforming virus insertion Over expressionOver expression Normal protein Over expressed Normal protein Acute Vs Slow-transforming Viruses Over expressed Mutant protein
- 22. DNA Viruses Adenoviridae Types2, 5, 12 Various solid Tumors Hepadanavirus Hepatitis B Virus (HBV) Hepatocellular carcinoma Herpesviridae Epstein-Barr Virus (EBV) Brukitt’s lymphoma, nasopharyngeal carcinoma Kaposi sarcoma Herpes Virus (KSHV) (HHV8) Kaposi sarcoma Polyomaviridae SV40, polyoma virus Various solid tumors Papillomaviridae HPV 6, 11, 16, 18 Bovine papilloma Virus Papilloma, Carcinoma Poxviridae Shope Fibromavirus Myxoma, Fibroma Classification of Oncogenic Viruses
- 23. Classification of OncogenicViruses Human oncogenic viruses and associated malignancies RNA oncogenic viurses Flaviviridae Hepatitis C Hepatocellular carcinoma Retroviridae
- 25. Classification of OncogenicViruses Human oncogenic viruses and associated malignancies RNA oncogenic viurses Flaviviridae Hepatitis C Hepatocellular carcinoma Retroviridae Alpharetroviruses 1 Rous Sarcoma Virus (RSV) Sarcoma 2 Rous Associated Virus (RAV) B-Cell lymphoma, erythroleukemia 3 Avian myeloblastosis virus (AMV) Myeloid/Erythroid leukemia 4 Avian erythroblastosis virus (AEV) Erythroid leukemia 5 Myelocytoma Virus (MC29) Myeloid leukemia
- 26. Classification of OncogenicViruses Human oncogenic viruses and associated malignancies RNA oncogenic viurses Retroviridae Betaretroviruses 1 Mouse mammary tumor virus (MMTV) Mammary crcinoma 2 Jaagsiekte sheep retrovirus Lung carcinoma Gammaretroviruses 1 Murine leukemia virus (MuLV) Leukemia, Lymphoma 2 Feline leukemia virus Leukemia, lymphosarcoma 3 Feline sarcoma virus Sarcoma 4 Simian sarcoma Virus Sarcoma
- 27. Classification of OncogenicViruses Human oncogenic viruses and associated malignancies RNA oncogenic viurses Retroviridae Deltaretroviruses 1 HTLV-1 Adult T cell leukemia/lymphoma 2 Bovine Leukemia Virus B cell leukemia Epsilonretroviruses 1 Walleye dermal sarcoma virus Sarcoma
- 28. Viruses Causing HumanCancers Virus Family Virus Human Cancer Paillomaviridae Human Papilloma Virus Genital Tumors Squamous cell carcinoma Oropharyngeal carcinoma Herpesviridae Epstein-Barr Virus Nasopharyngeal carcinoma Burkitt’s lymphoma Hodgkin disease B cell lymphoma Human Herpes Virus 8 Kaposi Sarcoma Hepadnaviridae Hepatitis B Virus Hepatocellular Carcinoma Flaviviridae Hepatitis C Virus Hepatocellular Carcinoma Retroviridae Human T cell Lymphoma Virus Adult T Cell lymphoma Human immunodeficiency virus AIDS related malignancies
- 29. Properties of TransformedCells • Changes in morphology – Change in cell morphology – Chromosomal alteration • Changes in cell metabolism – Increased rate of growth – Increased metabolic activity • Changes in growth characters – Loss of cell contact inhibitions – Formation of microtumors – Capacity to divide indefinitely in cultures • Changes in antigens – Appearance of new viral specific tumor Ags – Loss of surface Ags
- 30. Tumor Viruses DNA Viruses ViralOncoprotein Expression Viral Oncogene RNA Viruses Inactivation of Tumor Supreesor Genes Proto-Oncogene conversion Transforming Proviral Insertion Near Cellular Oncogene Non Transforming
- 31. DNA Viruses Hepatitis BVirus (HBV) Human Papillomavirus Adeno Virus
- 32. HPV (Human PapillomaVirus) • Small • Non-enveloped • Virion –Icosahedral • Genome – double stranded ,circular DNA
- 33. Epidemiology – HPV inducedcervical cancer is 2nd most common cancer worldwide – 16% of all female cancers are linked to HPV – Papilloma virus is found in 90% of women with cervical cancers
- 34. HPV Diseases • GenitalHPV is a very common STI usually causes no symptoms & goes away by itself sometimes causes serious illness. • HPV is responsible for – Almost all cases of genital warts and cervical cancer – 90% of anal cancers – 65% of vaginal cancers – 50% of vulva cancers – 35% of penile cancers – 60% of oropharyngeal cancers (cancers of the back of the throat, including the base of the tongue and tonsils). – 4 out of 5 people have at least one type of HPV at some time in their lives. It is sometimes called the “common cold” of sexual activity. – HPV infects both men and women.
- 36. HPV: Symptoms • Thoughmost HPV infections go away on their own, some HPV infections persist. HPV infections that don’t go away can cause changes in the cells in the infected area, which can lead to genital warts or cancer. • Genital warts usually appear as a small bump or groups of bumps in the genital area. They can be small or large, raised or flat, or clustered like a small piece of cauliflower. A healthcare provider can usually diagnose warts by looking at the genital area.
- 37. • Cervical cancerusually does not have symptoms until it is quite advanced and hard to treat. For this reason, it is important for women to get regular screening for cervical cancer. Screening tests can find early signs of disease so that problems can be treated before they ever turn into cancer. • Other cancers caused by HPV might not have signs or symptoms until they are advanced. These include cancers of the vulva, vagina, penis, anus, and cancers of the back of the throat, including the base of the tongue and tonsils (oropharynx).
- 38. Diagnosis • The Paptest can find abnormal cells on the cervix so that they can be removed before cancer develops. Abnormal cells often become normal over time, but can sometimes turn into cancer. These cells can usually be treated, depending on their severity and on the woman’s age, past medical history. • An HPV DNA test, which can find certain HPV types on a woman's cervixnd other test results.
- 39. Herpes Virus • HSV& CMV to transform cultured cells • HSV-2 cancer of uterine cervix • HSV-1 cancer of lip
- 40. • HSV-8 Kaposi’s sarcoma • CMV Kaposi’s sarcoma and carcinoma of prostate
- 41. Epstein-Barr Virus • Associatedwith Burkitt’s lymphoma & nasopharyngeal carcinoma • In children whose immune system is immunocompromised. • Cells grow indifinetly carry EB virus expresss Ag EBNA (Epstein Barr neucleic antigen) specific to virus Lymphocytes Lymphoblast Transformation
- 42. Hepatitis B Virus •Causes Hepatocellular Carcinoma. • Tumor cells contain Hepatitis B Virus DNA Poxvirus • Yaba virus benign histiocytoma in monkey • Shope fibroma viruses fibromas in rabbits Adenovirus • Some types (12, 18, 31) sarcomas in hamsters, not associated with human cancer.
- 43. RNA Oncogenic Viruses •All oncogenic RNA viruses except Hepatitis C Virus belongs to the family Retroviridae but all retroviruses are not oncogenic. • Mainly responsible for leukemias and sarcomas in their hosts. • Hepatitis C virus has been associated with primary hepatocellular carcinoma.
- 44. The Avian SarcomaLeukosis Complex • Are antigenically related viruses which induce avian leukosis (lymphomatosis, myeloblastosis and erythroblastosis viruses) or sarcoma in fowls (Rous sarcoma virus). Murine Leukosis Viruses • Murine leukemia and sarcoma viruses. Mammary Tumor Virus of Mice • Higher natural incidence of breast cancer. • Used to be known as the “Bittner virus” or “milk factor”. • Mammary cancer develops only in susceptible strains of mice, after a latent period of 6-12 months.
- 45. Leukosis-Sarcoma Viruses ofother animals • Number of viruses have been isolated from leukosis and sarcomas in various species of animals like cat, rat, guinea pig, hamster and monkey. Human T cell Leukemia Viruses (HTLV) • Produce T cell leukemia in human beings. • HTLV-1 causes T-cell leukemia • HTLV-2 induces hairy leukamia of T-cell type.
- 46. Viruses Associated Cancers DNAViruses Human papilloma viruses Genital (cervical, vulvar, penile) warts, may progres to carcinoma Epstein-Barr virus (EBV) Nasopharyngeal carcinoma, Burkitt’s lymphoma, B- cell lymphoma Human herpes 8 (HHV-8) Kaposi’s sarcoma Hepatitis B Virus (HBV) Primary hepatocellular carcinoma Merkel Cell polyomavirus Merkel cell carcinoma RNA Viruses Human T cell leukamia virus (HTLV-1) T-cell leukemia/lymphoma Hepatitis C virus (HCV) Primary hepatocellular carcinoma