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

描述（改编自研究者摘要）：包膜基因 编码一种糖蛋白，其功能是：1）连接到 CD 4受体，2）介导病毒和细胞膜的融合 在病毒进入时。 与CD 4的附着是表面（SU）的功能 信封的子单位。 融合是由跨膜（TM） 亚基，虽然SU部分也影响这个过程。 组织 培养研究表明， TM蛋白是多功能的，因为它影响细胞病理学， SU亚基的翻译修饰，以及 病毒粒子 本申请的假设是， TM的结构域具有控制SIV和HIV感染的功能结构域， 各自的易感宿主 该项目将分析 通过构建SIVmac和HIV-1分子， 在两个两亲性α螺旋中具有位点特异性突变的克隆 其与细胞裂解和与钙调蛋白结合有关。 将检测选定的SIVmac 239突变体的病毒载量、持久性 和致病潜力。 根据结果， 在这些实验中，将用猴子进行类似的实验。 感染了SIV/HIV嵌合体，这些嵌合体在 HIV-1的TM亚单位。 由于减毒SIVmac 1A 11具有两个过早的 终止密码子在TM亚基，建议研究的位点特异性 相关致病性SIVmac 239的突变可能表明， env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.