Functional and Structural Studies of Env-mediated Fusion

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DESCRIPTION (provided by applicant): Viral entry into the host cell is generally considered the initial step of infection, and as such, determining the mechanism of entry is critical for understanding the virus life cycle. In addition, the specificity of entry is one of the major determinants of viral tropism and pathogenesis. Viral entry has thus provided an attractive target for antiviral therapy, not only in terms of blocking virus attachment to the host cell, but also in terms of inhibiting envelope-mediated fusion. Also, understanding entry has proven essential for potential genetic therapy applications, in which many strategies call for targeting recombinant virus to a specific cell or tissue. The objective of this proposal is to outline a series of experiments designed to elucidate the mechanism of viral fusion, using the avian retrovirus Rous sarcoma virus (RSV) as a general model for viral entry. The specific goals are the following: 1) characterize envelope mutants which are defective for receptor-induced triggering; 2) investigate the role of pH in RSV entry: and 3) purify the components of the fusion apparatus for structure determination.