1. © Elsevier, 2011.Principles of Molecular Virology Virus Pathogenesis How virus infection may injure the body How HIV infection causes AIDS How some viruses cause cancer Emergent viruses

2. © Elsevier, 2011.Principles of Molecular Virology Mechanisms of Cellular Injury Altered shape Detachment from the substrate Lysis Membrane fusion Membrane permeability Inclusion bodies Apoptosis

3. © Elsevier, 2011.Principles of Molecular Virology Viruses and Immunodeficiency - HIV and AIDS

4. © Elsevier, 2011.Principles of Molecular Virology HIV and AIDS HIV infects CD4 + cells CD4 + cells are constantly being eliminated by HIV infection while the body is constantly replacing them Over time, CD4 counts drop, leaving the body susceptible to the infections that define AIDS Antigenic variation is important in the biology of HIV

5. © Elsevier, 2011.Principles of Molecular Virology Virus-Related Diseases - SSPE Measles - subacute sclerosing panencephalitis (SSPE) (about 1 in 300,000 cases): – Virus replication continues at a low level, but defects in the envelope protein genes prevent the production of extracellular infectious virus particles – Lack of envelope protein production causes failure of the immune system to recognize and eliminate infected cells

6. © Elsevier, 2011.Principles of Molecular Virology Virus-Related Diseases - Dengue

7. © Elsevier, 2011.Principles of Molecular Virology Bacteriophages and Human Disease Stx1 and Stx2 toxin genes are encoded by lysogenic prophages in Escherichia coli Other bacterial virulence determinants are also encoded by lysogenic phages: Diphtheria toxin Streptococcus erythrogenic toxins Staphylococcus enterotoxins

8. © Elsevier, 2011.Principles of Molecular Virology Cell Transformation by Viruses Transformed cells have an altered phenotype: Loss of anchorage dependence Loss of contact inhibition Colony formation in semi-solid media Decreased requirements for growth factors

9. © Elsevier, 2011.Principles of Molecular Virology Cell Transformation by Viruses Transformation is mediated by proteins encoded by oncogenes: Oncogenes and proto-oncogenes Tumour suppressor genes DNA repair genes

10. © Elsevier, 2011.Principles of Molecular Virology Oncogenes

11. © Elsevier, 2011.Principles of Molecular Virology Oncogenes

12. © Elsevier, 2011.Principles of Molecular Virology Cell Transformation by Retroviruses Not all retroviruses are capable of transforming cells (e.g. HIV) Transduction Cis-activation Trans-activation

13. © Elsevier, 2011.Principles of Molecular Virology Cell Transformation by DNA Viruses Several families of DNA viruses are capable of transforming cells Interact with cellular proteins which have a negative regulatory role in cell proliferation - p53 and pRb

14. © Elsevier, 2011.Principles of Molecular Virology SV40 T-antigen Binds to p53, allows DNA replication

15. © Elsevier, 2011.Principles of Molecular Virology DNA Transforming Viruses Adenoviruses Human papillomavirus (HPV)

16. © Elsevier, 2011.Principles of Molecular Virology Viruses and Cancer Epstein Barr Virus (EBV) Hepatitis B Virus (HBV) Hepatitis C Virus (HCV) Human Herpesvirus 8 (HHV-8) Human Papillomaviruses (HPV) Human T-Cell Leukaemia Virus (HTLV)

17. © Elsevier, 2011.Principles of Molecular Virology New and Emergent Viruses Poliovirus - changed with time? Measles virus Smallpox virus

18. © Elsevier, 2011.Principles of Molecular Virology Arboviruses Yellow fever virus Hantaviruses West Nile virus Chikungunya virus

19. © Elsevier, 2011.Principles of Molecular Virology Zoonoses Many emergent virus diseases are zoonoses (transmitted from animals to humans) Ebola virus (1976) Severe acute respiratory syndrome (SARS) (2003)

20. © Elsevier, 2011.Principles of Molecular Virology Bioterrorism? Smallpox Haemorrhagic fevers - filoviruses and arenaviruses

21. © Elsevier, 2011.Principles of Molecular Virology Summary Virus pathogenesis is complex, variable, relatively rare Pathogenesis is determined by the balance between host and virus factors The immune system also plays a part in causing symptoms and damage Some viruses can transform cells so that they continue to grow indefinitely Approximate 20% of human cancers are thought to be due to viruses

22. © Elsevier, 2011.Principles of Molecular Virology Further Reading Best, S.M. (2008) Viral Subversion of Apoptotic Enzymes: Escape from Death Row. Annual Review of Microbiology 62: 171-192 Casadevall, A. and Pirofski, L.A. (2004) The weapon potential of a microbe. Trends in Microbiology, 12: 259–263 Coiras M., López-Huertas M.R., Pérez-Olmeda, M. and Alcamí, J. (2009) Understanding HIV-1 latency provides clues for the eradication of long-term reservoirs. Nature Reviews Microbiol. 7(11): 798-812 DeCaprio, J.A. (2009) How the Rb tumor suppressor structure and function was revealed by the study of Adenovirus and SV40. Virology 384(2): 274- 284 Donlan, R.M. (2009) Preventing biofilms of clinically relevant organisms using bacteriophage. Trends in Microbiol. 17(2): 66-72 Douek, D.C. et al. (2003) T cell dynamics in HIV-1 infection. Annual Review of Immunology, 21: 265–304 Forsman, A. and Weiss R.A. (2008) Why is HIV a pathogen? Trends Microbiol. 16(12): 555-560 Hay, S. and Kannourakis, G. (2002) A time to kill: viral manipulation of the cell death program. J Gen Virol. 83: 1547-1564 Jansen, K.U. and Shaw, A.R. (2004) Human papillomavirus vaccines and prevention of cervical cancer. Annual Review of Medicine, 55: 319–331 Kyle, J.L. and Harris E. (2008) Global spread and persistence of dengue. Ann Rev Microbiol. 62: 71-92 LaBeaud, A.D., Kazura, J.W. and King, CH. (2010) Advances in Rift Valley fever research: insights for disease prevention. Curr Opin Infect Dis. 23(5): 403-408 Racaniello, V.R. (2006) One hundred years of poliovirus pathogenesis. Virology. 344(1): 9-16 Randolph, S.E. and Rogers, DJ. (2010) The arrival, establishment and spread of exotic diseases: patterns and predictions. Nat Rev Microbiol. 8(5): 361-371 Sierra, S., Kupfer, B. and Kaiser, R. (2005) Basics of the virology of HIV-1 and its replication. J Clin Virol. 34(4): 233-244 Stephen, A., Mims, C.A. and Nash, A. (2000) Mims’ Pathogenesis of Infectious Disease, 5th ed. Academic Press, London. ISBN 0124982654 Thorley-Lawson, D.A. and Allday, M.J. (2008) The curious case of the tumour virus: 50 years of Burkitt's lymphoma. Nature Rev Microbiol. 6(12): 913-924 Weaver, S.C and Reisen, W.K. (2010) Present and future arboviral threats. Antiviral Res. 85(2): 328-345. Weiss, R.A. (2002) Virulence and pathogenesis. Trends in Microbiology, 10: 314–317 Whitehead, S.S., Blaney, J.E., Durbin, A.P. and Murphy, B.R. (2007) Prospects for a dengue virus vaccine. Nature Rev Microbiol. 5(7): 518-528