Poxviruses: Their Impact on Human Health, History, and Research. Don Gammon March 18, 2011. What is a Virus?. What is a Virus?.
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March 18, 2011
Discovery of antivirals against smallpox.Harrison SC, Alberts B, Ehrenfeld E, Enquist L, Fineberg H, McKnight SL, Moss B, O'Donnell M, Ploegh H, Schmid SL, Walter KP, Theriot J.Proc Natl Acad Sci U S A. 2004 Aug 3;101(31):11178-92
IMAGE FROM: Poxvirus tropism.McFadden G.Nat Rev Microbiol. 2005 Mar;3(3)Review.
Poxviruses are the largest of the Mammalian Viruses
Poxviruses were the first animal viruses to be:
survivors remain disfigured
Ramses V (died 1157 BC)
IMAGE FROM: http://www.microbiologybytes.com/virology/Poxviruses.html
Image adapted from: http://whqlibdoc.who.int/smallpox/9241561106_chp3.pdf
Cortés & Aztec Empire
Pizzaro & Inca Empire
By mid-17th century the population was ~1/20th that in 1492
Why did European settlers find a seemingly empty land?
Smallpox becomes the first and only infectious disease ever to be eradicated
Timeline image taken from: Smallpox: anything to declare?Smith GL, McFadden G.Nat Rev Immunol. 2002 Jul;2(7):521-7
Despite eradication of variola by 1979, threat of accidental or intentional release lingers
Variola virus an ideal bioweapon because:
Highly transmissible by aerosol route
High proportion of susceptible persons (no vaccination)
High morbidity and mortality (10-30%)
Diagnosis of disease difficult- last seen over 30 years ago
No licensed drugs for smallpox
Dec. 9 Americath, 1979- WHO declares smallpox eradicated
Reports of disseminated vaccinia in HIV-infected individualsFurther Challenges: Immunosuppression
IMAGE FROM: Pathogenesis and potential antiviral therapy of complications of smallpox vaccination.Bray M.Antiviral Res. 2003 Apr;58(2):101-14. Review
Mortality rates: 1-10 %
2003 Outbreaks: USA & DRC
See: Human monkeypox: an emerging zoonotic disease.Parker S, Nuara A, Buller RM, Schultz DA.Future Microbiol. 2007 Feb;2(1):17-34. Review.
of DNA viruses
Slow 5’-to-3’ elongation
Removal of drug residue by
3’-to-5’ exonuclease (proofreading)
Second round replication
Conclusions: CDV impedes DNA synthesis and is resistant to removal by viral DNA polymerase
For more information see: Mechanism of inhibition of vaccinia virus DNA polymerase by cidofovir diphosphate.Magee WC, Hostetler KY, Evans DH.Antimicrob Agents Chemother. 2005 Aug;49(8):3153-62.
The 3'-to-5' exonuclease activity of vaccinia virus DNA polymerase is essential and plays a role in promoting virus genetic recombination.Gammon DB, Evans DH.J Virol. 2009 May;83(9):4236-50.
Dr. G. Andrei
VACV DNA Polymerase
Hypothesis:A314T and/or A684V substitutions are responsible for CDVR phenotype
Cultured cellsPlaque Reduction AssayCrystal violet staining
1. Culture (days)
2. Fix and stain
3. Count plaques
Typical Plaque Reduction Assay America
Increasing drug concentration
Decreasing plaque numbers
Conclusion: A314T and A684V substitution mutations in the VACV DNA Polymerase
cause resistance to CDV
D. Gammon, unpublished data
*Infection with CDVR Virus
IMAGE FROM: Cidofovir resistance in vaccinia virus is linked to diminished virulence in mice.Andrei G, Gammon DB, Fiten P, De Clercq E, Opdenakker G, Snoeck R, Evans DH.J Virol. 2006 Oct;80(19):9391-401.
Late transcription factors
Intermediate transcription factors
Immune defense molecules
Early transcription factors
Adapted from Moss. Fundamental Virology, 2001
Research Projects America
1. Antiviral Drugs
2. Basic Virology
3. Viral Immunology
3. Oncolytic Virotherapy
Poxvirus Replication & Pathogenesis;
IMAGE FROM: Poxvirus immunomodulatory strategies: current perspectives.Johnston JB, McFadden G.J Virol. 2003 Jun;77(11):6093-100. Review
not replicate in normal
in human cells lacking
Adapted IMAGE FROM: Poxvirus tropism.McFadden G.Nat Rev Microbiol. 2005 Mar;3(3)Review.
*Cancer cells often lack a functional IFN pathway
Myxoma Virus Treatment
Myxoma Virus Treatment
Tumour signal (luciferase) ~ 10 days after
C. Irwin, unpublished data