CHANGES IN THE CYTOPLASMIC TAIL OF GP41 CONFER RESISTANCE TO TETHERIN/BST2

GP41 细胞质尾部的变化赋予对 Tetherin/BST2 的抗性

• 批准号: 8358174
• 负责人: David Evans
• 金额: $ 5.78万
• 依托单位: TULANE UNIVERSITY OF LOUISIANA
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-05-01 至 2012-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8358174
• 关键词: Cells; Cytoplasmic Tail; Endocytosis; Funding; Grant; HIV-1; HIV-2; Human; Integral Membrane Protein; Interferons; Lymphocyte; Macaca mulatta; National Center for Research Resources; Pathogenesis; Phenotype; Primates; Principal Investigator; Proteins; Research; Research Infrastructure; Resistance; Resources; SIV; Source; United States National Institutes of Health; Virus; Virus Replication; cost

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Tetherin (BST-2 or CD317) is an interferon-inducible transmembrane protein that inhibits virus release from infected cells. Whereas HIV-1 Vpu and HIV-2 Env antagonize human tetherin, most SIVs use Nef to antagonize the tetherin proteins of their simian hosts. Here we show that compensatory changes in the cytoplasmic domain of gp41 restore resistance to tetherin in a nef-deleted strain of SIV that regained a pathogenic phenotype in rhesus macaques. These changes facilitate virus release in the presence of rhesus tetherin, but not human tetherin, and enhance virus replication in interferon-treated lymphocytes. The changes in gp41 result in a selective physical association with rhesus tetherin, and the internalization and sequestration of rhesus tetherin by a mechanism that depends on a conserved endocytosis motif in gp41. These results are consistent with HIV-2 Env antagonism of human tetherin, and suggest that the ability to oppose tetherin is important for lentiviral pathogenesis.

这个子项目是许多利用资源的研究子项目之一 由NIH/NCRR资助的中心拨款提供。子项目的主要支持 而子项目的主要调查员可能是由其他来源提供的， 包括其它NIH来源。 列出的子项目总成本可能 代表子项目使用的中心基础设施的估计数量， 而不是由NCRR赠款提供给子项目或子项目工作人员的直接资金。 Tetherin（BST-2或CD 317）是干扰素诱导的跨膜蛋白， 抑制受感染细胞释放病毒。尽管HIV-1 Vpu和HIV-2 Env拮抗人类的tetherin，但大多数SIV使用Nef来拮抗其猿宿主的tetherin蛋白。在这里，我们表明，gp 41的胞质结构域的补偿性变化恢复耐tetherin的nef缺失株SIV，恢复了恒河猴的致病表型。这些变化有利于病毒释放的存在下，恒河猴拴，但不是人类拴，并增强干扰素处理的淋巴细胞中的病毒复制。gp 41的变化导致与恒河猴拴蛋白的选择性物理关联，以及通过依赖于gp 41中保守的内吞作用基序的机制内化和隔离恒河猴拴蛋白。这些结果与HIV-2 Env对人系链蛋白的拮抗作用一致，并表明对抗系链蛋白的能力对于慢病毒发病机制是重要的。