Most organisms make a significant effort to maintain the integrity of their genome during replication, encoding complex systems to ensure few mutations are made and passed on to the next generation. However, RNA viruses have the highest error frequencies observed in nature, and thrive under these conditions. Error-prone viruses such as hepatitis C virus, West Nile virus, and HIV are among the most successful pathogens on the planet and continue to challenge the development of therapies. As illustrated by HIV, viruses with error-prone replication often become resistant to anti-viral drugs. Our laboratory studies how these errors are made, the effect of the errors on the viral population, how genetic recombination can re-assort mutations, and the effect of viral diversity on trafficking and pathogenesis in infected animals.
The viral RNA dependent RNA polymerase involved in genome replication misincorporates nucleotides at a high frequency and lacks proofreading activity. With error frequencies approaching 1 mistake per 10,000 nucleotides copied, it is likely that each virus in the population differs from all of the other viruses by one or more mutations. Therefore, RNA viruses are thought to exist as a quasispecies or swarm. The most common outcome of these errors is debilitation of the virus, but occasionally, beneficial mutations arise. Under incredible selective forces within the infected host, the viruses with beneficial mutations survive and take over the population. Additionally, most RNA viruses can re-arrange their genome by genetic recombination, possibly resulting in the rescue of defective genomes, immune evasion, and the linking of drug resistance mutations.
Because of their high error and replication rates, it is thought that for some RNA viruses, every possible mutation is made every day within an infected host. However, only a small subset of viruses in this mixed population survives and continues to replicate. We are interested in the contraction and expansion of the quasispecies, both within an infected animal and in transmission between infected animals. Previously, we found that host barriers can limit viral quasispecies spread within an infected animal, possibly limiting the pathogenesis of viral infection by limiting the diversity of the population.
We are using hepatitis C virus, poliovirus, and yellow fever virus to study viral genome evolution, the acquisition of drug resistance mutations, genetic recombination, and the effect of viral diversity on pathogenesis. Our overall goal is to understand host and viral determinants of viral genome evolution, especially as they pertain to treatment failure.
RESEARCH INTERESTS
hepatitis C virus
poliovirus
yellow fever virus
virus-host interactions and pathogenesis
RECENT PUBLICATIONS
SK Kuss, CA Etheredge, JK Pfeiffer, "Multiple Host Barriers Restrict Poliovirus Trafficking in Mice" PLoS Pathogens, June 2008
Pfeiffer, J.K. and Kirkegaard, K., "Bottleneck-mediated quasispecies restriction during spread of an RNA virus from inoculation site to brain." Proc. Natl. Acad. Sci. USA, 103(14):5520-25, 2006
Pfeiffer, J.K. and Kirkegaard, K., "Increased Fidelity Reduces Poliovirus Fitness and Virulence under Selective Pressure in Mice" PLoS Pathogens, 1(2):e11, 2005
Pfeiffer, J.K. and Kirkegaard, K., "Ribavirin resistance in hepatitis C virus replicon-containing cell lines conferred by changes in the cell line or mutations in the replicon RNA" J. Virology, 79(4):2346-55, 2005
Pfeiffer, J.K. and Kirkegaard, K., "A single mutation in poliovirus RNA-dependent RNA polymerase confers resistance to mutagenic nucleotide analogs via increased fidelity" Proc. Natl. Acad. Sci. USA, 100(12):7289-94, 2003
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