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

巨噬细胞趋向性 HIV-1 进化的生物学和分子生物学

• 批准号: 10882245
• 负责人: SARAH BETH JOSEPH
• 金额: $ 38.22万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-25 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10882245
• 关键词: AIDS dementia; Address; Affinity; Alanine; Amino Acids; Attenuated; Autopsy; Binding; Biological Assay; Biology; Brain; Bypass; CCR5 gene; CD4 Positive T Lymphocytes; Cell Nucleus; Cell surface; Cells; Central Nervous System; Chromosome Mapping; Consensus; Data; Environment; Epidemic; Evolution; Face; Founder Effect; Genetic Determinism; Genetic Transcription; HIV-1; HIV-2; Human; Impairment; Individual; Infection; Inflammatory; Integration Host Factors; Knowledge; Length; Lymphoid; Macrophage; Maps; Microglia; Modeling; Molecular; Molecular Biology; Molecular Cloning; Molecular Conformation; Myeloid Cells; Nature; Neurologic; Organ; Other Genetics; Pathogenesis; Pathogenicity; Pathway interactions; Pattern; Phenotype; Population; Primate Lentiviruses; Proteins; Recombinants; Role; Sampling; Scanning; Solid; System; T-Cell Activation; T-Lymphocyte; Testing; Tropism; Unmarried person; Variant; Viral; Virus; Virus Diseases; Virus Replication; Work; cell type; density; env Gene Products; env Genes; pressure; receptor; transcriptome sequencing

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.

项目摘要 嗜巨噬细胞的HIV-1的生物学、进化和发病机制知之甚少。从历史上看，所有R5 （CCR 5嗜性）HIV-1毒株被认为是嗜巨噬细胞的。我们现在知道野生型/正常型 HIV-1的感染需要高密度的CD 4进入，从而将感染导向CD 4 + T细胞，这些细胞表达高水平的 CD 4密度，并避免感染表达低密度CD 4的巨噬细胞。巨噬 嗜性代表了一条进化路径，病毒沿着该路径沿着进化出更有效地利用低亲和力的能力。 CD 4的密度进入，使骨髓细胞现在成为复制的目标。这条进化之路是 其次是最常见的中枢神经系统，其中CD 4 + T细胞是罕见的，这种表型的演变是 与艾滋病相关的痴呆症。已经进行了几次尝试来绘制遗传决定因素， 巨噬细胞嗜性，矛盾的是，这些经常被鉴定为R5中的共有氨基酸。 T嗜性病毒群体。此外，除了推断与CD 4更好的结合外，对该分子还一无所知。 Env蛋白如何进化成嗜巨噬细胞的机制。同样，HIV-1如何在 大脑中建立分区感染的可能性很大程度上是模糊的。我们对选择性压力 在髓样细胞内的压力可能选择进入表型以外的额外进化，其中这种压力可能 已经在其他灵长类慢病毒中选择了Vpx。这些问题的答案将有助于寻找潜在的 中枢神经系统中的储存库，这最终可能对于成功治愈HIV-1很重要。在这个应用程序中，我们提供 广泛的初步数据，开始解决这些问题，并描述了一个机构的工作，将显着 推进了我们对这种最具致病性的HIV-1进化变体的认识。