Role of Vpu in HIV1 Particle Exit

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DESCRIPTION (provided by the applicant): This proposal focuses on the role of viral protein U (Vpu) in viral particle exit. Our long term goal is to generate a comprehensive picture that describes the molecular mechanism of HIV particle release and the role that Vpu plays in that process. Our experiments are centered around the interaction between Vpu and a novel cellular protein designated Vpu binding protein (Ubp). This novel cellular protein is a member of a protein superfamily that contain repetitive copies of a motif, termed the TPR motif, that facilitates specific protein-protein interaction. Our preliminary data also indicate that Ubp interacts specifically with Gag. This is likely to be significant since the ultimate indirect target of Vpu is likely to be a component of Gag. Additional preliminary data indicates that the normal function of Ubp is to regulate the multiprotein chaperone complex by interacting with the C-terminal regulatory domain of Hsp70. There are several complementary goals of this proposal. We plan to examine in more detail Vpu-Ubp interaction and Ubp-Gag interaction and the role that these protein-protein associations play in Vpu-mediated particle exit. In addition, we will extend our observations which indicate that Ubp regulates protein folding and determine the relationship of this activity to Vpu-mediated particle release and Ubp-Gag interaction. In a second ostensibly separate biological activity, Vpu facilitates the degradation of CD4. Some proposed experiments will determine whether Ubp plays a role in that activity of Vpu. Additional genetic experiments will be carried out to determine the nature of second site revertants that arise following the propagation of primary Vpu mutants.