MOLECULAR DETERMINANTS OF CELL DEATH BY HIV1

PI已经从感染者身上分离出HIV-1病毒，尽管 相对较高的病毒载量，没有表现出临床 进展 其中一些病毒似乎在CD 4+细胞中复制良好。 淋巴细胞单细胞杀伤（CD 4-SCK）试验由 本申请人的方法，但表现出较低水平的诱导的细胞病变效应。 从这些人身上分离出的其他病毒可以复制， 在CD 4-SCK测定中诱导更大的细胞病变效应。 PI建议： (1)为了产生这些HIV-1分离物的分子前病毒克隆， 重复观察到的细胞杀伤表型;（2） 使用在致细胞病变和非致细胞病变之间构建的重组病毒 变异，以确定细胞病变效应的分子决定因素， CD 4-SCK测定和NOD/LtSz-scid小鼠模型。(3)以确定 鉴定的细胞病变决定簇在以下方面的潜在意义： 非进展患者的发病过程。

The PI has isolated HIV-1 viruses from infected humans that, despite relatively high viral loads, do not exhibit evidence of clinical progression. Some of these viruses appear to replicate well in a CD4 lymphocyte single cell killing (CD4-SCK) assay designed by the applicant, but exhibit lower levels of induced cytopathic effects. Other viruses isolated from these individuals replicate comparably but induce greater cytopathic effects in CD4-SCK assay. The PI proposes: (1) To generate molecular proviral clones of these HIV-1 isolates that duplicate the observed phenotypes with respect to cell killing; (2) To use recombinant viruses constructed between cytopathic and noncytopathic variants to identify the molecular determinants of cytopathic effect in the CD4-SCK assay and in a NOD/LtSz-scid mouse model. (3) To determine the potential significance of the identified cytopathic determinant in the course of pathogenesis in the non-progressor patients.