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Viral infection of host cells requires that the virus gain access to the cytoplasm and/or nucleus to accomplish subsequent steps in the viral replication cycle. Situated between the virus and its final destination are the cell plasma or endosomal membranes. While the molecular processes involved in membrane penetration by enveloped viruses have been analyzed in some detail, analogous events occurring during cell entry by nonenveloped viruses are currently less well understood. Adenovirus is a nonenveloped, double stranded DNA virus which serves as a model to study nonenveloped virus membrane penetration. Adenovirus (Ad) binds to cells via interactions between its fiber protein and its primary receptor (e.g., CAR or CD46). Secondary interactions between the Ad penton base and alpha(v) integrins on the cell surface triggers clathrin mediated internalization of the Ad. Once inside endosomes, the Ad capsid undergoes a conformational change which coincides with endosomal escape.
We have recently shown that under conditions mimicking that of early endosomes (e.g., lowered pH) the Ad capsid undergoes a conformational change resulting in the release of proteins from the capsid vertex. One of these proteins, protein VI, has been shown to possess membrane lytic activity. Future studies are aimed at A) further defining the role of protein VI in adenovirus membrane penetration and B) understanding the molecular basis for the partial disassembly of the capsid at lowered pH.
The mechanism of protein VI mediated membrane disruption is being explored using a variety of biophysical techniques to study the interaction of protein VI with model membranes and to determine structural changes that occur in protein VI upon membrane interaction. Studies of the disassembly of the Ad capsid will employ a combination of biophysical and genetic approaches. These studies will ultimately improve our understanding of the mechanistic details of cell entry by nonenveloped viruses.
Selected Publications
Horne WS, Wiethoff CM, Cui C, Wilcoxen KM, Amorin M, Ghadiri MR, Nemerow GR. (2005) Antiviral cyclic d,l-alpha-peptides: Targeting a general biochemical pathway in virus infections. Bioorg Med Chem. 13(17):5145-53.
Wiethoff CM, Wodrich H, Gerace L, Nemerow GR. (2005) Adenovirus protein VI mediates membrane disruption following capsid disassembly. J Virol. 79(4):1992-2000.
Search PubMed for a complete listing of Chris Wiethoff's publications
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