Human oncogenic viruses

1. Human oncogenic viruses

2. Nearly 20% of all cancers worldwide are attributed to viruses

3. Oncogenic virusesare viruses that produce tumors in their hosts (natural or experimental) and induce malignant transformation of cell cultures. • Tumor viruses: the DNA tumor viruses and the RNA tumor viruses. • Common aspect of their life cycle: the ability to integrate their own genome into that of the host cell.

4. Transformationis the introduction of inheritable changes in a cell causing changes in the growth phenotype and immortalisation. • Cancers are the result of a disruption of the normal control on cell growth and proliferation. • Properties of cancer cells: • immortality; • uncontrolled growth; • undifferentiation; • spread into and destroy surrounding tissues; • spread to other parts of the body.

5. Transformation by a virus is changes in the biologic functions of a cell that result from regulation of the cell by viral genes and that confer on the infected cell certain properties characteristic of neoplasia. • Transformed cell is a cell in which a virus takes up residence and alters its properties.

6. Francis Peyton Rous (1879-1970) • Rous is the first person to show that a virus could cause cancer in animals. • He demonstrated that a virus (Rous sarcoma virus) can cause cancer in chickens (1911). • For his discovery the Rous sarcoma virus F.P.Rous won the Nobel Prize in 1966.

7. Silber L.A. (1894-1966) - author of the viral-genetic theory of carcinogenesis

8. Cellular proto-oncogenes usually encode proteins that function in DNA replication. • Normally, they are not expressed in a cell since cells would multiply to repair damage, for example after a wound or operation. • They can be transformed in oncogenes only after being altered such as: • mutation or • coming under the control of a highly active promotor. • Oncogenesare cellular genes that influence cell growth and differentiation and code fora protein that potentially can transform a normal cell into a malignant cell. • Viral oncogenes are cellular oncogenes that become incorporated into the virus by recombination. • A virus may cause cancer in two ways: - it may carry an oncogene into a cell or - it may activate a cellular proto-oncogene as promotor.

9. BASIC MECHANISM OF CELL GROWTH TRANSFORMATIONBY DNA VIRUSES • Viral DNA integration into cellular genome occurs only rarely and is not a normal part of the virus life cycle. • Integrated viral DNA carries an oncogene into a cell and permanently expresses “early” viral genes B. Viral DNA integration destabilises cellular genome and/or activates adjacent cellular oncogenes

10. Discoverers of viral reverse transcriptase. The Nobel Prize in Physiology or Medicine 1975 • They discovered reverse transcriptase, a DNA-polymerase enzyme that transcribes RNA into DNA. • Their discovery showed that the DNA's genetic information, which ordinarily travels from DNA to RNA, can also travel in the other direction, allowing viruses to replicate the RNA into the DNA of otherwise healthy calls, which can cause some forms of cancer. Howard M. Temin (1934-1994) David Baltimore (1938)

11. The reverse transcriptase of retroviruses catalyses a series of reactions to convert the single-stranded RNA genome of viruses into double-stranded DNA for host-cell integration.

12. BASIC MECHANISM OF CELL GROWTH TRANSFORMATIONBY RETROVIRUSES • Provirus integrates into cellular genome as a normal part of virus life cycle. • Integrated provirus activates adjacent cellular oncogene. B. Provirus carries a “captured” cellular oncogene. C. Provirus-coded protein activates cellular genes.

13. The general classes of oncogenesencode: - growth factors, - membrane receptors, - signaling proteins, conveying signals from the outside of the cell to the interior, - DNA binding proteins - factors which interact in gene regulation and replication, - and other regulatory proteins.

14. ANTI-ONCOGENES (Tumor suppressor genes) • They stop the cell multiplying or doubling. • If one of these genes becomes damaged and stops working, then the cell may carry on and on multiplying and becomes immortal. • Tumour suppressor gene p53 normally • stops cells with other damaged genes from reproducing to allow for DNA damage repair • or causes the cell to undergo apoptosis if the damage cannot be repaired.

15. p53 is a tumor suppressor • It is referred to as The Guardian of the Genome since it regulates of the DNA damage control system. • p53 is damaged or missing in most human cancers. • How does p53 work in a functional cell? • A few of p53 molecules - in a healthy cell. • DNA becomes damaged DNA replication results The rise in p53 stops DNA replication.

16. p53 is a transcription factor. 1. p53 binds to a specific site on the chromosomes and switches on other genes and these, in turn, shut down DNA replication. 2. Hepatitis C virus causes hepatocellular carcinoma by taking the tumor suppressor out of action by complexing it in an inactive form that cannot bind to the specific site on DNA. 3.Papilloma viruses bind p53 and direct it to a protease that destroys it. 3 1 2

17. Human oncogenic viruses RNA-viruses • Family Retroviridae (HTLV-1, HTLV-2) • Family Flaviviridae (hepatitis virus C) DNA-viruses • Family Hepadnaviridae (hepatitis virus B) • Family Herpesviridae (HSV 2, Epstain Bar virus, HV 8) • Family Papillomaviridae(18 types)

18. Family Retroviridae. Genus Deltaretrovirus.Human T lymphotropic viruses(HTLV-1, HTLV-2) - HTLV was the first unequivocal human cancer virus to be identified by Yorio Hinuma and colleagues in 1981. - HTLV are characterized by the proliferation of mainly CD4+ T-lymphocytes and the development of adult T cell leukemia (in some Japanese islands, the Caribbean, Latin America and Africa). HTLV is sexually and parenterally transmitted.

19. Natural course from the infection of HTLV-I to onset of aneuploid adult T-cell leukaemia(ATL) • HTLV-I promotes proliferation of infected cells by actions of Tax • Proliferation of infected cells is controlled by cytotoxic T-cells. • Alternations in the host genome lead to the onset of ATL. • After an asymptomatic period of 20–40 years, ATL-cells ('flower cells', with flower-shaped nuclei) emerge in approximately 5% of infected individuals. Most HTLV-1-infected individuals remain life-long asymptomatic carriers.

20. Family Flaviviridae. Hepatitis virus C Hepatocellular сarcinomadevelops inabout 50% ofpersons with chronicinfection over a period of 10 to 30 years

21. Hepatitis BVirus 30-90 % of infected young patients less than five years and 10-15% of infected patients of five years and older go on to the chronic infection. Chronic hepatitis leads to hepatocellular carcinoma in up to a quarter of patients. Liver cancer

22. Possible mechanisms of hepatitis B virus involvement in oncogenesis: (1) Integration viral DNA induces synthesis of HBxAg which binds p53. (2) Repression of the cell beta-interferon promoter. (3) Integration within a cell cycle control gene, cyclin. (4) Integration near a hormone response gene, thus altering control. (5) Deletion of the anti-oncogene p53. However, the strongest association with cancer occurs with chronic liver disease.

23. Herpes Simplex Virus • Prior infection with HSV-2 is associated with cervical intraepithelial neoplasia and carcinoma of the uterine cervix. • Smoking and exposure to a number of genital infections increases the probability of developing cervical cancer. • Epidemiology: HSV-2 is sexually transmitted.

24. Epstein Barr Virus (EBV) • Burkitt's lymphoma (African manifestation) • Nasopharyngeal cancer (common Chinese & SE Asian manifestation) • B cell lymphomas in immune suppressed individuals (organ transplantation or HIV) • Oral hairy leukoplakia (in HIV-infected patients)

25. Burkitt's lymphoma is a tumor of the jaw and face found in children. • There is probably a genetic reason possibly involving an association with malaria.

26. Nasopharyngeal cancer is a tumor of the epithelium of the upper respiratory tract • South China, Alaska, Tunisia, east Africa. • genetic predisposition • environmental cofactor involved.

27. Oral hairy leukoplakia results in lesions in the mouth (whitish, corrugated or hairy, adherent plaques, lateral margins of the tongue)

28. Kaposi’s Sarcoma (HHV 8) KS is a systemic disease that can present with cutaneous lesions with or without internal involvement. KS can involve the oral cavity, lymph nodes, and viscera of gastrointestinal and respiratory tract. Morphologies of cutaneous lesions: macular, patch, plaque, nodular. The AIDS-related KS lesions affect the upper trunk, face, and oral cavity Transmission: through saliva (by kissing), organ transplantation, blood transfusion.

29. Papillomaviruses (HPV) • Transmission: • sexually • fingers-genital contact • direct contact through abrasion • perinatally from mother to child. • Papillomaviruses are associated with: • human penile, anal, vaginal, uterine and cervical carcinomas • genital warts that can convert to carcinomas • carcinomas of skin, esophagus, larynx and lung. • condilomas, papilomas, warts • HPV cause 16% of female cancers worldwide and 10% of all cancers. • Vulvar, penile and cervical cancers - types 16 and 18.

30. Harald zur Hausen (born March 11, 1936) • He has done research on cancer of the cervix, where he discovered the role of papilloma viruses. • He identified HPV16 and HPV18 in cervical cancers in 1983-4. This research directly made possible the development of a vaccine which was introduced in 2006. • For this discovery he received the Nobel Prize in Physiology or Medicine 2008.

31. Papillomaviruses HPV have a circular ds DNA protected by protein capsid. 170 types are pathogenic for human. 18 types are involved in cancer. 270000 women die from cervical cancer every year

32. Cervical cancer • Cervical cancer does not have symptoms until it is quite advanced. • For this reason, it is important for women to get routine Pap tests regularly for cervical cancer.

33. Genital warts • Warts may appear within weeks or months after sexual contact with an infected person. • They usually appear as small bumps or groups of bumps, usually in the genital area. They can be raised or flat, single or multiple, small or large, and sometimes cauliflower shaped. • They can appear on the vulva, in or around the vagina or anus, on the cervix, and on the penis, scrotum, groin, or thigh. • If left untreated, genital warts may go away, remain unchanged, or increase in size or number.

34. Cancer of the tounge Oral papillomas Papillomaviruses Infectious warts Condilomas Papillomas

35. Laryngeal papillomatosis • Symptoms: • Adults • hoarseness, or a strained or breathy voice. • Size and placement of the tumors dictate the change in the person's voice. • Breathing difficulties may occur but more commonly are found in children. • Children • trouble swallowing, noisy breathing, and chronic cough. • Noisy breathing may be a stridor, which can sound like a whistle or a snore, and is a sign that the laryngeal or tracheal parts of the airway are narrowing. • Oral HPV infection is associated with oropharyngeal cancer.

36. Human papilloma virus vaccines 1. Gardasil, marketed by Merck (L protein of 6, 11, 16 and 18 types). 2. Cervarix, marketed by GlaxoSmithKline (L protein of 16 and 18 types). Types 16 and 18 cause 99,7% cervix cancer cases. Types 6 and 11 cause 90% of genital warts. Both are delivered in three shots over six months (0-1-6 months). Cervarix efficacy is proven for 7.4 years while Gardasil - for 5 years.

37. Principal cellular and soluble antitumoral components of innate immune system • Dendritic cells • Complement • Neutrophils • Transforming growth • Macrophages factor beta (TGFß) • NK cells • Cytokines (IL-10, IL-12) • T cells • γ-Interferon • B cells Dendritic cell and T cells are attacking cancer cell

38. Mechanisms responsible for death of tumor cells • T cells, which recognize tumor antigens, became activated and produce interferon IFNγ and lymphotoxin, which activate natural killer (NK) and macrophages. • NK cells release perforin- and granzyme-containing granules, which causes apoptosis. • Macrophages release tumor necrosis factor TNFγ and other cytokines as well as reactive oxygen intermediates. • Antibodies (Abs) to tumor-specific antigens (TSAs) induce arrest of tumor growth or mediate antibody-dependent cellular toxicity (ADCC) by arming effector cells (NK cells or macrophages). macrophage

39. Coordinated tumor immunity Immune-mediated rejection of established Her-2 positive breast tumors requires CD4+ and CD8+ T cells, NK T cells, neutrophils, macrophages, antibodies (Ab’s), Fc receptors, IFN-γ, and perforin.

40. Two outcomes of interactions between tumor cells and immune cells in the tumor microenvironment Cytokines secreted by tumor and immune cells can either promote tumor development and tumor cell survival or exert antitumor effects IL-10, through antiinflammatory effects, and IL-12, through activation of CTLs and NK cells and expression of cytotoxic mediators, can lead to tumor suppression.

41. The three Es of cancer immunoediting: host protective versus tumor sculpting actions of immunity. Following cellular transformation and the failure of intrinsic tumor suppressor mechanisms, a developing tumor is detected by the immune system and its ultimate fate is determined by whether or not it is eliminated by the host protective actions of immunity (Elimination phase), maintained in a dormant or equilibrium state (Equilibrium phase) or escapes the extrinsic tumor suppressor actions of immunity by either becoming non-immunogenic or through the elaboration of immunosuppressive molecules and cells (Escape phase

42. Preparation of Tumor-infiltrating lymphocytes