Karla A. Kirkegaard
Department of Microbiology and Immunology
Stanford University School of Medicine
Stanford, CA 94305-3402
1987 Searle Scholar
Cell Biology, Genetics and Biochemistry of RNA Viral PropagationFor many subcellular viruses and parasites, RNA, not DNA, is the carrier of genetic information. This has several interesting consequences for the genetics and biology of the virus. Poliovirus serves as a model to increase our understanding of positive-strand RNA viruses for which no vaccine is available and which remain a significant health hazard: examples include other picornaviruses -- rhinoviruses, coxsackieviruses, and echoviruses -- as well as more distantly related positive-strand RNA viruses such as hepatitis C virus, dengue virus, and West Nile virus.
Our Laboratory is interested in the mechanism of the RNA-dependent RNA amplification utilized by positive-strand RNA viruses, such as poliovirus, rhinoviruses, hepatitis C virus and dengue virus in their replication. Genetically, this process is highly error-prone, due to the low fidelity of the viral RNA polymerases. This low fidelity results in a "quasispecies" of RNA genomes, even within any individual infected cell. It is in this milieu that new mutations that might confer advantage, such as drug resistance, arise. A recent emphasis is to learn how to suppress the diversity of such viruses, and the outgrowth of potentially drug-resistant viruses, by understanding the nature of this intracellular mileau. The cell biology of RNA amplification is also a focus of the laboratory. All positive-strand viruses of eukaryotes replicate their genomes on intracellular membranes, which are rearranged and exploited differently by different viruses. Poliovirus, which has been the subject of most of the laboratory's investigations, induces the formation of double-membraned vesicles that resemble cellular autophagosomes.
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