Viruses and cancer

1. Viruses and cancer

2. Viruses and cancer Brief background on cell cycle factors Rb and E2F example Enquist et al., Principles of Virology, ASM, 2004 Example: DNA damage during G1 P53 recognizes DNA damage and activates P21 (p53 recognizes certain types of DNA mismatches) P21 binds and inactivates the cyclin-CDK complex which has already begun to be produced in response to different signals DNA repaired, p53 decreases, P21 no longer blocks cyclin-CDK, cell cycle progression P53 act as a checkpoint controller to stop cell-cycle progression

3. Inactivation of p53 by papillomavirus proteins HPV E6 protein Enquist et al., Principles of Virology, ASM, 2004

4. HPV E5 protein increases EGF receptor concentration E5 binds vacuolar ATPase and inhibits acidification of endosomes Enquist et al., Principles of Virology, ASM, 2004

5. E7 protein of HPV Similar proteins of other viruses these proteins bind Rb complex and prevent Rb from negatively regulating E2f SV40 virus LT (Large T antigen) Adenovirus E1a protein Adenovirus not oncogenic in humans (yes in hamsters) In humans the virus infection & release kills cells, but a defective virus might be oncogenic in humans Enquist et al., Principles of Virology, ASM, 2004 SV40 LT disassembly of Rb-E2f complex

6. Antiviral Treatment Strategies (Chapter 44) • Inhibitors of viral replication • every step in viral replication is potentially a target • targeting host cell functions is generally not feasible (toxicity)

7. Agents developed by an empirical approach • Interferons • natural products discovered in 1957 • Interferons assist the immune response • inhibit viral replication within host cells • activate natural killer cells and macrophages • increase antigen presentation to lymphocytes • induce resistance of host cells to viral infection. • Type I interferons • Interferon-(produced by leukocytes; induced by viruses) • Interferon-(produced by fibroblasts & epithelial cells; induced by viruses) • Type II interferon • Interferon-(induced by antigens and mitogens)

8. Effects of interferon therapy • Fatigue • Fever • Myalgias • Bone marrow suppression • Neuropsychiatric problems • Treatment for hepatitis C Virus (HCV) infection • Formerly used for HBV

9. Ribavirin • Purine nucleoside analog • Inhibits many RNA viruses and some DNA viruses • Influenza A and B • Measles • Respiratory Syncytial Virus • Several different mechanisms of action • Inhibits viral polymerases • Reduces GTP levels • Impairs 5’ capping of viral mRNAs • Lack of potency at nontoxic levels

10. Steps in virus replication targeted by current drugs and drugs in development

11. Virus entry Enfuvitide - HIV fusion inhibitor Binds to gp41 region that folds back onto itself Prevents fusion of membranes Very specific to HIV

12. Virus entry • used to prevent influenza infections • blocks penetration and uncoating of influenza A virus 75% effective if given prior to viral exposure 50% effective if given after 1st signs of infection Rimantadine = analog

13. Amantadine and rimantadine affect M2’s function as an ion channel Following endocytosis, acidification of endosomes occurs Then M2 can function as ion channel Acidification within virion drives viral disassembly

14. Viral genome replication Acyclovir - result of rational drug design targeting herpesviruses involved in DNA synthesis and function Viral TK much more efficient than cellular TK in this reaction (so drug is specific to infected cells) However, acyclovir has no effect on latency

15. Comparison of intravenous acyclovir and placebo for inhibition of virus shedding in immunocompetent individuals with first episode of genital herpes Comparison of oral acyclivir (blue) and placebo (red) for suppression of recurrent genital herpes.

16. Viral genome replication inhibits herpes virus enzymes involved in DNA and RNA synthesis and function inhibits herpes virus DNA polymerase Directly inhibits herpesvirus and cytomegalovirus DNA polymerase Ganciclovir is effective against CMV compared to acyclovir, although it is also more toxic (cellular TK uses drug better too).

17. Cidofovir is a relatively broad-spectrum anti-DNA virus drug inhibits viral DNA polymerase papovaviruses, adenoviruses, herpesviruses iridoviruses, and poxviruses

18. Anti-HIV drugs: nucleoside reverse transcriptase inhibitors (NRTI) nonnucleoside reverse transcriptase inhibitors (NNRTI) Delaviridine Efavirenz Nevirapine

19. Anti-HIV drugs: Protease inhibitors Peptidomimetic inhibitors Ritonavir But unexpected activity: Cytochrome P450 3A4 inhibitor Saquinavir HAART = highly active antiretroviral therapy at least 3 drugs in combination 2 nucleoside inhibitors plus a NNRTI or a protease inhibitor

20. Virus release Neuraminidase inhibitors - influenza virus neuraminidase (NA) release of virus from envelope cleaves sialic acid (NA has enzymatic activity) Inhibitors prevent efficient spread of virus from cell to cell

21. Vaccines and antisera (Chapter 45) Immunoglobulins passive immunization limitations sometimes antiviral antibody titers not high enough contamination with other infectious agents need to use early after exposure often this is not possible some viruses have a limited extracellular phase herpesviruses, enteroviruses used against: Cytomegalovirus Hepatitis B Rabies Respiratory Syncytial Virus Vaccinia (smallpox) Varicella zoster