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

描述（由申请人提供）：为了建立生产性感染，HIV-1必须抵消抑制病毒复制的宿主因素。一种这样的限制因子是BST 2（也称为系链蛋白），其阻断新形成的病毒体从宿主细胞释放。该提议扩展了最近的初步数据，该数据鉴定了进化枝B Vpu的C-末端附近的保守残基W76，其对于Vpu抵消BST活性和增强病毒体释放的能力是关键的，但对于Vpu降解BST 2或降低其在细胞表面上的浓度的能力是不确定的。我们将调查这种活动的机制，测试的假设，即W76有助于Vpu的能力，以取代BST 2从网站的病毒体组装在质膜的平面，可能是通过破坏与病毒体组装膜微区之间的关系。此外，我们将确定这种功能是否是其他缺乏W76的HIV-1进化枝（特别是进化枝C）的特征，如果是，则确定所涉及的关键残基。总之，所提出的实验应该更好地定义Vpu活性的新机制，并且它们应该确定该机制是进化枝B Vpu特有的还是Vpu蛋白质的更一般性质。

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.