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

这个子项目是利用资源的许多研究子项目之一。 由NIH/NCRR资助的中心拨款提供。对子项目的主要支持 子项目的首席调查员可能是由其他来源提供的， 包括美国国立卫生研究院的其他来源。为子项目列出的总成本可能 表示该子项目使用的中心基础设施的估计数量， 不是由NCRR赠款提供给次级项目或次级项目工作人员的直接资金。 Tetherin(BST-2或CD317)是一种干扰素诱导的跨膜蛋白， 抑制受感染细胞的病毒释放。虽然HIV-1VPU和HIV-2Env拮抗人类Tetherin，但大多数SIV使用Nef来拮抗它们宿主的Tetherin蛋白。在这里，我们展示了gp41胞浆区域的代偿性变化恢复了在猕猴中重新获得致病表型的nef缺失SIV菌株对tetherin的抵抗力。这些变化促进了在恒河猴Tetherin而不是人类Tetherin存在的情况下病毒的释放，并增强了干扰素处理的淋巴细胞中的病毒复制。Gp41的改变导致与恒河猴Tetherin的选择性物理结合，并通过一种依赖于gp41保守的内吞作用基序的机制使恒河猴Tetherin内化和隔离。这些结果与人类Tetherin对HIV-2 Env的拮抗作用是一致的，并表明对抗Tetherin的能力在慢病毒的致病过程中是重要的。

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.