HLA-associated control-lack of control in HIV infection

HLA相关控制-HIV感染缺乏控制

• 批准号: 7572880
• 负责人: PHILIP J GOULDER
• 金额: $ 42.25万
• 依托单位: UNIVERSITY OF OXFORD
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-09-15 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7572880
• 关键词: Address; Affect; Alleles; CD8B1 gene; Cytotoxic T-Lymphocyte Analysis; Disease; Disease Outcome; Epidemic; Epitopes; Funding; Future; Goals; Grant; HIV; HIV Infections; HIV vaccine; Immune; Investigation; Knowledge; Link; Outcome; Population; South Africa; Specificity; T-Cell Immunologic Specificity; T-Lymphocyte; Vaccines; Viral; Viremia; Work; base; cohort; comparative efficacy; design; insight; response

DESCRIPTION (provided by applicant): Particular HLA class I associations with differential viral set-points and rates of progression to HIV disease provide potential insights into the mechanisms by which CD8+ T cells can influence outcome in HIV infection. Certain alleles are associated with effective control, whilst others are linked to rapid progression. The starting hypothesis underlying these proposed studies is that the diversity of these HLA-associated HIV outcomes may be primarily related to differences in the particular epitopes targeted, which in turn dictate the efficacy of the CD8+ T cell response. During the initial funding period of this grant, we focused our investigations in Durban, South Africa, in a region critically affected by the epidemic. We have identified the principal HLA class I alleles associated with low viral set-point, and those associated with high viral set-point; we have undertaken a comprehensive empirical analysis of the CD8+ T cell responses and have defined the majority of the epitopes that are characteristically targeted in this infected population. Initial studies of HLAB* 57 and B*5801, the two alleles most strong associated with low viral set-point in this cohort, indicated a likely contributory mechanism by which immune control may be brought about. The proposed studies expand on these findings and consider additionally the CD8+ T cell specificities that are associated with high viral set-point. A central hypothesis of this proposed work is that the goal of an HIV vaccine should not be to generate as many CD8+ T cell responses as possible, but rather to induce only certain efficacious CD8+ T cell specificities. Equally important, CD8+ T cell responses that have an actively deleterious influence on immune control need to be omitted from such a vaccine. The specific aims of the proposed studies are to a) define the epitopes that are targeted by the few alleles that are associated with extremes of outcome; b) identify which of these epitopes are associated with successful or unsuccessful control of viremia; and, c) to determine what is the likely evolutionary destiny, and therefore vaccine-relevance of these epitopes.

描述（由申请人提供）：特定的 HLA I 类与不同的病毒设定点和 HIV 疾病进展速率的关联为 CD8+ T 细胞影响 HIV 感染结果的机制提供了潜在的见解。某些等位基因与有效控制相关，而其他等位基因则与快速进展相关。这些拟议研究的起始假设是，这些 HLA 相关 HIV 结果的多样性可能主要与特定目标表位的差异有关，这反过来又决定了 CD8+ T 细胞反应的功效。在这笔赠款的初始资助期间，我们将调查重点放在南非德班，该地区受疫情影响严重。我们已经确定了与低病毒设定点相关的主要 HLA I 类等位基因，以及与高病毒设定点相关的主要 HLA I 类等位基因；我们对 CD8+ T 细胞反应进行了全面的实证分析，并确定了该感染人群中的大多数特征性靶向表位。 HLAB* 57 和 B*5801（这两个等位基因与该队列中的低病毒设定点关系最密切）的初步研究表明，这可能是实现免疫控制的一种促成机制。拟议的研究扩展了这些发现，并另外考虑了与高病毒设定点相关的 CD8+ T 细胞特异性。这项拟议工作的中心假设是，HIV 疫苗的目标不应该是产生尽可能多的 CD8+ T 细胞反应，而应该仅诱导某些有效的 CD8+ T 细胞特异性。同样重要的是，这种疫苗需要消除对免疫控制产生积极有害影响的 CD8+ T 细胞反应。拟议研究的具体目标是 a) 定义与极端结果相关的少数等位基因所针对的表位； b) 确定这些表位中的哪些与成功或不成功的病毒血症控制相关； c) 确定可能的进化命运，从而确定这些表位的疫苗相关性。