A RECEPTOR MEDIATING CELL-CELL AND CELL-AIDS VIRUS INTERACTIONS

CD4与第II类MHC的相互作用对细胞是必不可少的。 免疫反应，而CD4与HIV包膜的关联是 这是艾滋病病毒感染的关键一步。对这一概念的理解 参与这两个矛盾过程的分子机制形成了 这是这项提议的基础。描述了定义角色的实验 在伴随胸腺发育的选择事件中的CD4和CD8。 将嵌合的CD4和CD8基因导入转基因小鼠将 允许对细胞内信号进行分析 胸腺细胞参与I类MHC，以及这些信号在 第二类分子的结合。另一系列实验是 被描述为研究CD4介导的准确的分子事件 HIV与靶细胞的结合和进入。证据是 蓄积表明靶细胞上除CD4以外的其他分子 可能需要，以促进有效的病毒进入。我们想要隔离 编码这些因子的基因，以提供对 艾滋病毒进入的机制超出了其最初与CD4的关联。这 也可能允许构建对艾滋病毒敏感的转基因小鼠 感染。最后，CD4可能不会作为被动的附着部位 HIV，但可能在导致病毒的融合事件中发挥重要作用 进入。我们已经设计了一系列实验来询问CD4是否 仅在允许病毒在靶细胞中紧密结合时才需要 膜，还是CD4是否在结合后也起着重要作用， 促进艾滋病毒的融合和进入。总而言之，这些基因 而生化实验可能最终会允许解剖 导致艾滋病毒与细胞膜融合的分子事件。

The interaction of CD4 with class II MHC is essential for the cellular immune response, while the association of CD4 with the HIV envelope is an essential step in AIDS virus infection. An understanding of the molecular mechanisms involved in these two paradoxical processes form the basis for this proposal. Experiments are described to define the role of CD4 and CD8 in the selection events that accompany thymic development. The introduction of chimeric CD4 and CD8 genes into transgenic mice will permit an analysis of the intracellular signals generated when a thymocyte engages class I MHC, and how these signals differ upon engagement of class II molecules. A separate series of experiments are described to examine the precise molecular events by which CD4 mediates the association and entry of HIV with the target cell. Evidence is accumulating to suggest that molecules other than CD4 on the target cell may be required to facilitate efficient viral entry. We wish to isolate the genes encoding such factors in order to provide new insight into the mechanisms of entry of HIV beyond its initial association with CD4. This may also permit the construction of transgenic mice susceptible to HIV infection. Finally, CD4 may not serve as a passive attachment site for HIV, but may play an important role in the fusion events leading to virus entry. We have designed a series of experiments to ask whether CD4 is required solely to allow the close apposition of the virus in target cell membrane, or whether CD4 also plays an important role postbinding, facilitating the fusion and entry of HIV. Taken together, these genetic and biochemical experiments may ultimately permit a dissection of the molecular events leading to the fusion of HIV with the cell membrane.