HLA-associated control-lack of control in HIV infection

HLA相关控制-HIV感染缺乏控制

• 批准号: 7074789
• 负责人: PHILIP J GOULDER
• 金额: $ 50.27万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-02-01 至 2010-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7074789
• 关键词: AIDS; AIDS /HIV diagnosis; AIDS vaccines; Africa; HIV infections; MHC class I antigen; biotechnology; blood chemistry; cellular immunity; clinical research; communicable disease control; cytotoxic T lymphocyte; epidemiology; genetic strain; histocompatibility typing; human subject; immunoregulation; outcomes research; pathologic process; polymerase chain reaction; vaccine development; virus antigen; virus load

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类与不同病毒设定点和HIV疾病进展率的相关性为CD 8 + T细胞影响HIV感染结局的机制提供了潜在的见解。某些等位基因与有效控制有关，而另一些则与快速进展有关。这些拟议研究的基础假设是，这些HLA相关的HIV结果的多样性可能主要与靶向的特定表位的差异有关，这反过来又决定了CD 8 + T细胞应答的功效。在这笔赠款的最初资助期间，我们将调查重点放在南非的德班，那里是受疫情严重影响的地区。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等位基因;我们对CD 8 + T细胞应答进行了全面的实证分析，并确定了该感染人群中特征性靶向的大多数表位。对HLAB* 57和B*5801（这两个等位基因在该队列中与低病毒设定点最强相关）的初步研究表明，可能存在免疫控制的可能贡献机制。拟议的研究扩展了这些发现，并额外考虑了与高病毒设定点相关的CD 8 + T细胞特异性。这项工作的核心假设是，HIV疫苗的目标不应该是产生尽可能多的CD 8 + T细胞应答，而是只诱导某些有效的CD 8 + T细胞特异性。同样重要的是，需要从这样的疫苗中省略对免疫控制具有积极有害影响的CD 8 + T细胞应答。拟议研究的具体目的是a）确定与极端结果相关的少数等位基因靶向的表位; B）鉴定这些表位中哪些与成功或不成功控制病毒血症相关;以及c）确定这些表位可能的进化命运，从而确定这些表位的疫苗相关性。