PHENOTYPE AND CORECEPTOR USE IN HIV-1 TRANSMISSION

I型人体免疫缺陷病毒（HIV-1）的性传播 占全球新感染病例的绝大多数。在大多数 在某些情况下，感染是由于病毒与 粘膜或上皮下层中的CD 4+靶细胞。艾滋病毒的相互作用- 1.细胞表面CD 4不足以使病毒进入; 然而，这表明感染还需要其他因素， 发生。最近的研究已经确定了几个相关的七- 作为病毒融合辅因子的跨膜受体 和进入。虽然这些辅助受体被实验室利用， 适应的HIV-1菌株，它们被初级 HIV-1的分离株仍然基本上未知。特别令人 疫苗开发的重要性在于确定这些受体是否 性传播的HIV-1病毒株所使用的，无论某些共同- 受体优先使用，以及这一过程是否可以 被这些受体的天然配体抑制。研究 本提案中概述的将直接评估共同受体 使用充分表征的 急性HIV-1感染期间从患者中分离的一组主要病毒 感染在初步研究中，我们评估了辅助受体的使用， 通过使用一组CD 4+细胞系稳定检测HIV-1原代分离株 表达每种已知的HIV-1共受体。另外我们有 开发了一种单循环互补试验，以确定是否 病毒包膜糖蛋白与每种HIV-1 辅助受体足以介导进入CD 4+细胞。使用 这些检测，该提案的目标是： 1)确定传播菌株使用的主要辅助受体 并将共受体的使用与病毒表型相关联， 对β-趋化因子阻断的敏感性。 2)为了确定HIV-1的主要传播株是否介导 通过包膜糖蛋白相互作用进入CD 4+细胞 与特定的辅助受体。 3)为了确定选择特定的病毒表型 在传播过程中与CD 4+上的辅助受体表达相关 靶细胞

Sexual transmission of human immunodeficiency virus type-I (HIV-1) accounts for the vast majority of new infections worldwide. In most cases, infection occurs as a result of interaction of the virus with CD4+ target cells in the mucosa or sub-epithelium. Interaction of HIV- 1 with CD4 on the cell surface is insufficient for viral entry; however, indicating that additional factors are required for infection to take place. Recent studies have identified several related seven- transmembrane receptors that function as co-factors for viral fusion and entry. Although these co-receptors are utilized by laboratory adapted strains of HIV-1, the extent to which they are used by primary isolates of HIV-1 remains largely unknown. It is of particular importance for vaccine development to determine whether these receptors are used by sexually transmitted strains of HIV-1, whether certain co- receptors are used preferentially and whether this process can be inhibited by the natural ligands for these receptors. The studies outlined in this proposal will directly evaluate the co-receptor requirements of transmitted strains of HIV-1 using a well-characterized panel of primary viruses isolated from patients during acute HIV-1 infection. In preliminary studies, we have evaluated co-receptor use by primary isolates of HIV-1 using a panel of CD4+ cell lines stably expressing each of the known HIV-1 co-receptors. In addition, we have developed a single-cycle complementation assay to determine whether interaction of the viral envelope glycoproteins with each of the HIV-1 co-receptors is sufficient to mediate entry into CD4+ cells. Using these assays, the goals of the proposal are: 1) To determine the primary co-receptor(s) used by transmitted strains of HIV-1 and to correlate co-receptor use with viral phenotype and sensitivity to beta-chemokine blocking. 2) To determine whether primary, transmitted strains of HIV-1 mediate entry into CD4+ cells by interaction of their envelope glycoproteins with specific co-receptors. 3) To determine whether selection for a particular viral phenotype during transmission correlates with co-receptor expression on CD4+ target cells.