ROLE OF THE SIV/HIV TRANSMEMBRANE SUBUNIT OF ENV IN AIDS

描述(改编自研究人员摘要)：包膜基因 SIV和HIV编码一种糖蛋白，其功能是：1)附着在 2)介导病毒与细胞膜的融合 在病毒入侵期间。附着在CD_4上是表面(SU)的函数 信封的子单元。Fusion受制于跨膜(TM) 亚单位，尽管SU部分也影响这一过程。组织 培养研究表明，细胞胞质内结构域 TM蛋白是多功能的，因为它影响细胞病理学，在细胞死亡后。 SU亚基的翻译修饰和极化释放 病毒粒子。这一应用的假设是胞浆内的 TM的结构域具有控制SIV和HIV感染的功能结构域 各自易受感染的宿主。本项目将分析 前面提到的通过构建SIVmac和HIV-1分子的功能 在两个两亲性α螺旋中具有位点特异性突变的克隆 它们与细胞裂解和钙调蛋白结合有关。 选定的SIVmac239突变株将接受病毒载量、持久性测试 以及恒河猴的致病潜能。基于以下结果 这些实验，类似的实验将在猴子身上进行 感染了SIV/HIV嵌合体，该嵌合体在 HIV-1的TM亚基。因为减毒的SIVmac1A11有两个早产儿 停止密码子在TM亚基上的研究，建议对特定部位进行研究 相关致病基因SIVmac239的突变可能证明这一点 包膜蛋白的结构域是致病的重要决定因素。

DESCRIPTION (Adapted from investigator's abstract): The envelope gene of SIV and HIV encodes a glycoprotein that functions to: 1) attach to the CD4 receptor, and 2) mediates fusion of the viral and cell membrane during viral entry. Attachment to CD4 is a function of the surface (SU) subunit of envelope. Fusion is governed by the transmembrane (TM) subunit, although the SU portion also affects this process. Tissue culture studies have demonstrated that the intracytoplasmic domain of the TM protein is multi-functional in that it influences cytopathology, post- translational modification of the SU subunit, and polarized release of virions. The hypothesis of this application is that the intracytoplasmic domain of TM has functional domains that govern SIV and HIV infection in the respective susceptible host. This project will analyze the previously mentioned functions by constructing SIVmac and HIV-1 molecular clones with site-specific mutations in two amphipathic alpha helices which have been implicated in cell lysis and binding to calmodulin. Selected mutants of SIVmac239 will be tested for viral load, persistence and pathogenic potential in rhesus monkeys. Based upon the outcome of these experiments, similar experiments will be performed with monkeys infected with SIV/HIV chimeras containing site-specific mutations in the TM subunit of HIV-1. Because the attenuated SIVmac1A11 has two premature stop codons in the TM subunit, the proposed studies of site-specific mutations of the related pathogenic SIVmac239 may demonstrate that this domain of env is an important determinant of pathogenesis.