Transcript Document

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. 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): 274284
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
Principles of Molecular Virology
© Elsevier, 2011.