Grant: Operating Grant

Poxviruses are large viruses that cause infections in many organisms. These viruses still cause some disease in humans, although the most famous poxvirus, variola virus, was eradicated 40 years ago using a worldwide campaign of vaccination using the related vaccinia virus. Although epidemic smallpox is gone, and the variola virus stocks are now stored under armed guard, it would be possible to remake ("reactivate") live variola virus using a combination of old genetic methods and new DNA synthesis technologies. The vaccinia virus that was in the smallpox vaccine also appears to have gone wild again, back into buffalo and cattle in India and South America, and may be evolving into a new human pathogen. Thus while smallpox has been eradicated, poxviruses continue to be a threat to human health. In fact, vaccines and drugs continue to be developed and stockpiled, to guard against the reappearance of smallpox or a related disease. My research concerns itself with trying to understand how poxvirus DNA is copied, what virus and cell proteins catalyze these reactions, and how this can lead to the production of recombinant viruses. These replication reactions are of great interest because the majority of antiviral drugs inhibit the virus replication machinery, and our past work with some of these compounds has helped others develop new smallpox drugs. Recombinant viruses are produced when two different viruses infect the same cell, and they are of interest because the resulting progeny contain a mix of both parent virus DNAs and can sometimes exhibit new and dangerous properties. A lot of recombination is also seen in poxvirus reactivation reactions of the kind that could be used to revive smallpox. By studying vaccinia virus recombination, our work will provide insights into what role recombination might play in the evolution of existing and new poxviruses and what biosecurity risks might be posed by poxvirus reactivation technologies.