STRUCTURE/FUNCTION STUDY OF HIV AND SIV CORECEPTORS

描述：这个最初的独立研究项目将集中在 CCR5及其相关的HIV-1和SIV的结构/功能关系 共同受体。HIV和SIV开始进入CD4+靶细胞 通过病毒包膜糖蛋白与细胞表面的CD4结合。我们 而另一些研究表明，趋化因子受体随后介导了 导致病毒与细胞膜融合的短暂步骤。《CCR5》 分子是M嗜性HIV-1毒株的主要共同受体 最常见的是在个体之间传播。然而，决定因素 CCR5与HIV-1囊膜糖蛋白的相互作用基本保持不变 未知。在具体目标1中，我们将继续确定 与HIV-1和SIV共同受体有关的CCR5胞外环 活动。我们将使用几种生物检测方法来阐明 病毒融合中的功能相关残基。在具体目标2中，我们将 确定不同HIV-1和SIV共受体的功能结构域 共享一个共同的结构。在具体目标3中，我们将确定绑定 新的抗CCR5单抗和抑制CCR5的药物的结合部位 CCR5介导的融合和进入。然后我们将绘制细胞外表面的地图 通过单抗交叉竞争分析获得CCR5。总而言之，这些研究将 确定CCR5和相关辅助受体中重要的元件 用于病毒融合和进入，并表征它们在 CCR5表面。CCR5单抗和Low靶标的研究 分子量化合物将促进药物抑制剂的发展 共受体功能。我们的调查将提供详细的分子 HIV-1生命周期中的一个重要步骤，以及抑制它的方法 通过抗病毒药物。

DESCRIPTION: This initial independent research project will focus on the structure/function relationships in CCR5 and related HIV-1 and SIV co-receptors. The entry of HIV and SIV into CD4+ target cells is initiated by the binding of the viral envelope glycoproteins to cell surface CD4. We and others have demonstrated that chemokine receptors then mediate essential transitory steps leading to viral-to-cell membrane fusion. The CCR5 molecule is the principle co-receptor for M-tropic HIV-1 strains that are most commonly transmitted between individuals. However, the determinants of CCR5 interactions with the HIV-1 envelope glycoproteins remain largely unknown. In Specific Aim 1, we will continue to identify residues in the extracellular loops of CCR5 that are important for HIV-1 and SIV co-receptor activity. Several biological assays will be used to elucidate the role of functionally relevant residues in viral fusion. In Specific Aim 2, we will determine if the functional domains of different HIV-1 and SIV co-receptors share a common structure. In Specific Aim 3, we will determine the binding sites of new anti-CCR5 MAbs and pharmacological agents that inhibit CCR5-mediated fusion and entry. We will then map the extracellular surface of CCR5 by a MAb cross-competition analysis. Together, these studies will identify the elements in CCR5 and related co-receptors that are important for viral fusion and entry, and characterize their spatial distribution on the CCR5 surface. The studies of the targets on CCR5 for MAbs and low molecular weight compounds will facilitate the development of inhibitors of co-receptor function. Our investigations will provide a detailed molecular picture of an essential step in the HIV-1 life cycle, and ways to inhibit it by antiviral agents.