Role of HIV-1 Env Diversity in Cellular Tropism

HIV-1 包膜多样性在细胞趋向性中的作用

• 批准号: 7024426
• 负责人: Maureen M Goodenow
• 金额: $ 47.37万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-04-01 至 2010-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7024426
• 关键词: AIDS therapy; HIV envelope protein gp120; HIV infections; antiAIDS agent; biochemical evolution; blood tests; chemokine receptor; chimeric proteins; clinical research; cytokine; genetic mapping; helper T lymphocyte; host organism interaction; human immunodeficiency virus 1; human subject; human tissue; macrophage; microorganism immunology; molecular site; protein protein interaction; protein structure function; thymus; virus genetics; virus infection mechanism; virus receptors

DESCRIPTION (provided by applicant): HIV-1 displays complex phenotypes for coreceptor usage and repertoire of host cells. Types of cells targeted by HIV-1 can have a profound impact for disease progression, provide different intracellular milieus that can facilitate evasion of immunity, modulation of variants within the viral quasispecies, and provide reservoirs for latent infection. Macrophage tropism by variants of HIV-1 is regulated at the level of entry by viral use and host cell expression of coreceptors CCR5 or CXCR4. Genetic determinants of coreceptor usage map to HIV- 1 env, in particular hypervariable domain V3 in Env gp120. CXCR4-mediated entry can be distinct for different cell types. The rationale for the proposed studies is that CXCR4-using viruses develop in vivo, and contribute to disease progression. The hypothesis is that complex, discontinuous determinants that map to regions of Env outside V3 modulate interactions between Env gp120 and CXCR4 in a cell-type dependent manner. Three Specific Aims are proposed: 1. Map genotypic evolution in vivo of envelope gp120 V1-V5 regions; 2. Map determinants in gp120 that confer D-X4 phenotype in different primary cells; and 3. Determine functional impact of gp120-mediated coreceptor usage on macrophages and thymocytes. Studies are cross-sectional, including primary subtype B, A, and D viruses from peripheral blood, and longitudinal, including viruses from peripheral blood prior to and following antiretroviral therapy and from peripheral blood and tissue compartments. The proposed studies use innovative technologies and longitudinal evaluation of genotype, phenotype, and function of envelopes from individuals with well-defined clinical variables to identify determinants among viruses that emerge in vivo prior to development of late stage disease. The proposed studies are significant for defining unique phenotypic characteristics of envelopes that use CXCR4 for infection of macrophages and thymocytes, immune biomarkers that aid clinicians in defining the optimal timing for initiation of ART in children, development of novel, cell-type specific inhibitors of chemokine receptor interactions, and designing therapeutic vaccines with effects across subtypes and coreceptor usage to prevent evolution of viruses with expanded tropism and pathogenesis.

描述（由申请人提供）：HIV-1显示用于托管细胞的共肽使用和曲目的复杂表型。由HIV-1靶向的细胞类型可以对疾病进展产生深远的影响，提供不同的细胞内环境，可以促进逃避免疫，调节病毒准确性中的变体，并为潜在感染提供储藏。 HIV-1变体的巨噬细胞向向向向向向向向向向向the，在通过病毒使用和宿主细胞表达CCR5或CXCR4的宿主细胞表达下进行调节。对艾滋病毒-1 ENV的共受体使用图的遗传决定因素，特别是ENV GP120中的高变量域V3。对于不同的细胞类型，CXCR4介导的条目可能与众不同。拟议的研究的理由是，使用CXCR4的病毒在体内发展，并有助于疾病进展。该假设是，映射到v3外部区域的复杂，不连续的决定因素，以依赖性的方式调节ENV GP120和CXCR4之间的相互作用。提出了三个具体目的：1。包膜GP120 V1-V5区域的体内基因型进化； 2。gp120中的MAP决定因素，在不同原代细胞中赋予D-X4表型；和3。确定GP120介导的共受体使用对巨噬细胞和胸腺细胞的功能影响。研究是横断面的，包括外周血和纵向的原发性亚型B，A和D病毒，包括抗逆转录病毒治疗前后的外周血的病毒以及外周血和组织室。拟议的研究使用创新技术和对具有明确定义的临床变量个体的基因型，表型和功能的纵向评估，以鉴定在晚期疾病发展之前在体内出现的病毒的决定因素。拟议的研究对于定义使用CXCR4感染巨噬细胞和胸腺细胞，免疫生物标志物的信封的独特表型特征非常重要受体相互作用，并设计具有跨亚型和共纤接受的作用的治疗疫苗，以防止随着趋势和发病机理扩大的病毒进化。