Biology and Molecular Biology of the Evolution of Macrophage-Tropic HIV-1

项目摘要 嗜巨噬细胞HIV-1的生物学、进化和发病机制尚不清楚。从历史上看，所有R5 (CCR5嗜性)HIV-1毒株被认为是嗜巨噬细胞。我们现在知道野生型/正常型 HIV-1的感染需要高密度的CD4进入，从而将感染导向高表达高水平的CD4+T细胞 降低CD4的密度，并避免感染巨噬细胞，因为巨噬细胞表达的是低密度的CD4。巨噬细胞 趋向性代表了一条进化路径，病毒沿着这条路径进化出更有效地利用低价病毒的能力 进入的CD4密度，使髓系细胞现在成为复制的目标。这条进化之路是 其次是中枢神经系统，那里的CD4+T细胞很少见，这种表型的进化是 与艾滋病毒相关性痴呆症有关。已经进行了几次尝试，以绘制出遗传决定因素的图谱 巨噬细胞的趋向性和矛盾的是，它们经常被确定为R5中的共同氨基酸 嗜T病毒种群。此外，除了推断更好地与cd4结合外，人们对这种分子一无所知。 包膜蛋白如何进化为亲巨噬细胞的机制。同样，HIV-1是如何在 脑部能否建立分区感染很大程度上还不清楚。关于选择性压力是如何产生的，我们知之甚少 在髓系细胞内可能选择进入表型之外的额外进化，其中这种压力可能 在其他灵长类慢病毒中选择了VPX。对这些问题的回答将为寻找潜在的 这可能最终对成功治愈HIV-1起到重要作用。在此应用程序中，我们提供 广泛的初步数据，开始解决这些问题，并描述了一系列将显著 促进我们对HIV-1这种最具致病性的进化变种的了解。

Project Abstract The biology, evolution, and pathogenesis of macrophage-tropic HIV-1 is poorly understood. Historically, all R5 (CCR5-tropic) HIV-1 strains were considered macrophage-tropic. We now know that the wild type/normal form of HIV-1 requires a high density of CD4 for entry, thus directing infections to CD4+ T cells, which express high densities of CD4, and avoiding infection of macrophages, which express low densities of CD4. Macrophage tropism represents an evolutionary path along which the virus evolves the ability to more efficiently use a low density of CD4 for entry, allowing myeloid cells to now become targets for replication. This evolutionary path is followed most commonly within the CNS, where CD4+ T cells are rare, and evolution of this phenotype is associated with HIV-associated dementia. Several attempts have been made to map genetic determinants of macrophage tropism and paradoxically these have often been identified as the consensus amino acid in the R5 T-tropic virus population. Also, other than inferring better binding to CD4, nothing is known about the molecular mechanisms of how the Env protein evolves to become macrophage-tropic. Similarly, how HIV-1 colonizes the brain to establish a compartmentalized infection is largely obscure. Little is known about how selective pressures within myeloid cells may select for additional evolution beyond the entry phenotype, where such pressure may have selected for Vpx in other primate lentiviruses. Answers to these questions will inform the search for a latent reservoir in the CNS, which may ultimately be important for a successful HIV-1 cure. In this application we provide extensive preliminary data that start to address these questions and describe a body of work that will significantly advance our knowledge of this most pathogenic evolutionary variant of HIV-1.