The overall goal of the research proposed in this revised application is to study the cellular and viral processes involved in the initial stages of the infectious cycle of herpes simplex virus type 1 (HSV-1) and influenza A virus. As outlined by Dr. Helenius, the mission of a virus particle is to deliver the genome and accessory proteins into a host cell in a replication-competent form. The virus particle must enter the cytosol, and from the cytosol the genome and accessory proteins of HSV-1 and influenza viruses have to move into the nucleus for replication. The applicant proposes to particularly focus on the interaction of incoming HSV-1 capsids with elements of the cytoskeleton, and the mechanisms by which capsids are targeted to interact with nuclear pore complexes. With regard to influenza virus, the applicant proposes to study how the viral ribonucleoproteins (vRNPs) are transported into and out of the nucleus. Biological, biochemical and genetic approaches will be used to address the overall goals of the project. The specific goals of the proposed study are 1) to analyze the mechanisms by which incoming HSV-1 capsids interact with the peripheral cytoskeleton, associate with dynein, dynactin and microtubules, and how the capsids move to the nuclear pores; 2) to determine how HSV-1 capsids and influenza virus vRNPs interact with nuclear pores, and how the genome is transported through the pore; 3) to analyze the mechanism by which newly assembled influenza virus vRNPs are exported from the nucleus to the cytosol in infected cells. By addressing these largely neglected processes, the applicant hopes to unravel new principles and mechanisms relevant for the general understanding of virus-cell interactions. The results are also likely to provide new insight on the larger questions of cell tropism and pathogenesis. Moreover, the information may suggest novel antiviral strategies, and allow informed application of viruses as vehicles for gene transfer.
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