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: 7388819
• 负责人: Maureen M Goodenow
• 金额: $ 46.85万
• 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/7388819
• 关键词: Biological Markers; CCR5 gene; CXCR4 gene; Cell Communication; Cell Surface Receptors; Cells; Cellular Tropism; Characteristics; Child Development; Clinical; Complementarity Determining Regions; Complex; Cross-Sectional Studies; Development; Disease; Disease Progression; Evaluation; Evolution; Genetic Determinism; Genotype; HIV; HIV Envelope Protein gp120; HIV-1; Immune; Immune System Diseases; Immunity; Individual; Infection; Localized; Maps; Measures; Mediating; Mutation; Pathogenesis; Phenotype; Recombinants; Role; Staging; Time; Tissues; Tropism; Variant; Viral; Virus; antiretroviral therapy; cell type; chemokine; chemokine receptor; cytokine; design; env Glycoproteins; in vivo; inhibitor/antagonist; innovative technologies; latent infection; macrophage; novel; peripheral blood; prevent; therapeutic vaccine; thymocyte

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 对于辅助受体的使用和宿主细胞的功能表现出复杂的表型。 HIV-1靶向的细胞类型可以对疾病进展产生深远影响，提供不同的细胞内环境，促进逃避免疫、调节病毒准种内的变异，并为潜伏感染提供储存库。 HIV-1 变体的巨噬细胞趋向性在进入水平上通过病毒使用和辅助受体 CCR5 或 CXCR4 的宿主细胞表达进行调节。辅助受体使用的遗传决定因素映射到HIV-1 env，特别是Env gp120中的高变域V3。 CXCR4 介导的进入对于不同的细胞类型可能是不同的。拟议研究的基本原理是，使用 CXCR4 的病毒在体内发育，并导致疾病进展。假设映射到 V3 外部 Env 区域的复杂、不连续的决定因素以细胞类型依赖性方式调节 Env gp120 和 CXCR4 之间的相互作用。提出了三个具体目标： 1. 绘制包膜 gp120 V1-V5 区域的体内基因型进化图谱； 2. 绘制 gp120 中赋予不同原代细胞 D-X4 表型的决定簇； 3. 确定 gp120 介导的辅助受体使用对巨噬细胞和胸腺细胞的功能影响。研究是横向的，包括来自外周血的初级亚型 B、A 和 D 病毒，纵向的研究包括来自抗逆转录病毒治疗之前和之后的外周血以及来自外周血和组织区室的病毒。拟议的研究使用创新技术和对具有明确临床变量的个体的基因型、表型和包膜功能的纵向评估，以确定在晚期疾病发展之前体内出现的病毒的决定因素。拟议的研究对于确定使用 CXCR4 感染巨噬细胞和胸腺细胞的包膜的独特表型特征、帮助临床医生确定儿童开始 ART 的最佳时机的免疫生物标志物、开发新型细胞类型特异性趋化因子抑制剂具有重要意义。受体相互作用，并设计具有跨亚型和辅助受体使用效果的治疗性疫苗，以防止具有扩大的趋向性和发病机制的病毒进化。