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

HIV-1 Vpu C 末端参与增强病毒粒子释放

• 批准号: 8790372
• 负责人: John C. Guatelli
• 金额: $ 20.88万
• 依托单位: VETERANS MEDICAL RESEARCH FDN/SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-08-05 至 2016-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8790372
• 关键词: Affect; C-terminal; Cell membrane; Cell surface; Cells; Charge; Data; Down-Regulation; Gagging; HIV-1; Head; Immunoblotting; Immunofluorescence Microscopy; Infection; Integral Membrane Protein; Integration Host Factors; Lipid Bilayers; Lipids; Liposomes; Location; Maps; Measures; Membrane; Membrane Microdomains; Modeling; NMR Spectroscopy; Phospholipids; Property; Proteins; Recruitment Activity; Site; Surface; Testing; Tryptophan; Viral; Virion; Virus; human PHEMX protein; mutant; prevent; public health relevance; research study; vpu Protein

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.

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子。其中一种限制因子是BST2（也称为tetherin），它可以阻止新形成的病毒粒子从宿主细胞释放出来。该建议扩展了最近的初步数据，确定了B支Vpu W76的C端附近的保守残基，这对于Vpu抵消BST活性和增强病毒粒子释放的能力至关重要，但对于Vpu降解BST2或降低其在细胞表面的浓度的能力是必不可少的。我们将研究这种活性的机制，验证W76有助于Vpu从质膜平面上的病毒粒子组装位点取代BST2的假设，可能是通过破坏与病毒粒子组装相关的膜微域之间的关系。此外，我们将确定该功能是否是缺乏W76的其他HIV-1进化支（特别是进化支C）的特征，如果是的话，确定所涉及的关键残基。总之，提出的实验应该更好地定义Vpu活性的新机制，他们应该确定这种机制是特异性的进化枝B Vpu还是Vpu蛋白的更普遍的性质。