Involvement of the C-terminus of HIV-1 Vpu in Enhancement of Virion Release

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DESCRIPTION (provided by applicant): In order to establish a productive infection, HIV-1 must counteract host factors that inhibit viral replication. One such restriction factor is BST2 (also called tetherin), which blocks the release of newly formed virions from the host cell. This proposal expands on recent preliminary data identifying a conserved residue near the C- terminus of clade B Vpu, W76, which is critical for Vpu's ability to counteract the activity of BST and enhance virion release, yet is dispensable for Vpu's ability to degrade BST2 or reduce its concentration on the cell surface. We will investigate the mechanism of this activity, testing the hypothesis that W76 contributes to the ability of Vpu to displace BST2 from sites of virion assembly in the plane of the plasma membrane, possibly by disrupting the relationships between the membrane microdomains associated with virion-assembly. Moreover, we will determine if this function is a feature of other HIV-1 clades (specifically clade C) which lack W76, and if so, identify the critical residues involved. Together, the proposed experiments should better define a new mechanism of Vpu activity, and they should determine whether this mechanism is specific to clade B Vpu or is a more general property of Vpu proteins.