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Virus Pathogenesis • How virus infection may injure the body • How HIV infection causes AIDS • How some viruses cause cancer • Emergent viruses Principles of Molecular Virology © Elsevier, 2011. Mechanisms of Cellular Injury • Altered shape • Detachment from the substrate • Lysis • Membrane fusion • Membrane permeability • Inclusion bodies • Apoptosis Principles of Molecular Virology © Elsevier, 2011. Viruses and Immunodeficiency HIV and AIDS Principles of Molecular Virology © Elsevier, 2011. 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 Principles of Molecular Virology © Elsevier, 2011. 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 Principles of Molecular Virology © Elsevier, 2011. Virus-Related Diseases - Dengue Principles of Molecular Virology © Elsevier, 2011. 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 Principles of Molecular Virology © Elsevier, 2011. 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 Principles of Molecular Virology © Elsevier, 2011. Cell Transformation by Viruses Transformation is mediated by proteins encoded by oncogenes: • Oncogenes and proto-oncogenes • Tumour suppressor genes • DNA repair genes Principles of Molecular Virology © Elsevier, 2011. Oncogenes Principles of Molecular Virology © Elsevier, 2011. Oncogenes Principles of Molecular Virology © Elsevier, 2011. Cell Transformation by Retroviruses Not all retroviruses are capable of transforming cells (e.g. HIV) • Transduction • Cis-activation • Trans-activation Principles of Molecular Virology © Elsevier, 2011. 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 Principles of Molecular Virology © Elsevier, 2011. SV40 T-antigen Binds to p53, allows DNA replication Principles of Molecular Virology © Elsevier, 2011. DNA Transforming Viruses • Adenoviruses • Human papillomavirus (HPV) Principles of Molecular Virology © Elsevier, 2011. 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) Principles of Molecular Virology © Elsevier, 2011. New and Emergent Viruses • Poliovirus - changed with time? • Measles virus • Smallpox virus Principles of Molecular Virology © Elsevier, 2011. Arboviruses • • • • Yellow fever virus Hantaviruses West Nile virus Chikungunya virus Principles of Molecular Virology © Elsevier, 2011. Zoonoses • Many emergent virus diseases are zoonoses (transmitted from animals to humans) • Ebola virus (1976) • Severe acute respiratory syndrome (SARS) (2003) Principles of Molecular Virology © Elsevier, 2011. Bioterrorism? • Smallpox • Haemorrhagic fevers - filoviruses and arenaviruses Principles of Molecular Virology © Elsevier, 2011. 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 Principles of Molecular Virology © Elsevier, 2011. Further Reading Best, S.M. (2008) Viral Subversion of Apoptotic Enzymes: Escape from Death Row. 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