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 巨噬细胞 - 热带HIV-1的生物学，进化和发病机理知之甚少。从历史上看，所有R5 （CCR5-热带）HIV-1菌株被认为是巨噬细胞 - 热带。我们现在知道野生类型/正常形式 HIV-1的CD4密度需要高密度才能进入，因此将感染引导到CD4+ T细胞，该细胞表达高 CD4的密度，并避免了巨噬细胞的感染，巨噬细胞表达CD4的密度低。巨噬细胞 向潮流代表了一种进化路径，该病毒会进化出更有效地使用低的能力 CD4的密度用于进入，允许髓样细胞成为复制的靶标。这种进化路径是 在CNS中最常见的是CD4+ T细胞很少的CNS，并且该表型的演变为 与HIV相关痴呆有关。已经尝试了绘制遗传决定因素的几次尝试 巨噬细胞的巨噬细胞和自相矛盾的是，这些经常被确定为R5中的共有氨基酸 T-递归病毒种群。同样，除了推断出更好的结合与CD4之外，分子没有什么了解 Env蛋白如何演变成巨噬细胞 - 热带的机制。同样，HIV-1如何殖民 大脑建立隔室感染是晦涩的。关于选择性压力的知之甚少 在髓样细胞内可能会选择以外的进化表型，而这种压力可能 在其他灵长类动病毒中选择了VPX。这些问题的答案将为您寻找潜在的搜索 中枢神经系统中的水库，这对于成功的HIV-1治疗可能最终很重要。在此应用中，我们提供 广泛的初步数据开始解决这些问题，并描述了将大大的工作 促进我们对HIV-1最致病的进化变体的了解。