Promiscuous presentation of HLA class I restricted, HIV derived CTL epitopes

HLA I 类限制性 HIV 衍生 CTL 表位的混杂呈现

• 批准号: 7074644
• 负责人: CHRISTIAN BRANDER
• 金额: $ 42.72万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-06-15 至 2010-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7074644
• 关键词: HIV infections; MHC class I antigen; T cell receptor; alleles; antigen antibody reaction; antigen presentation; clinical research; cytotoxic T lymphocyte; human subject; immune response; immune response genes; pathologic process; patient oriented research; virus antigen

DESCRIPTION (provided by applicant): Promiscuous presentation of HLA class I restricted, HIV derived CTL epitopes CTL mediated cellular immunity is considered an important arm of the host defense against HIV infection and a number of HLA class I alleles have been associated with slow or fast HIV disease progression. Despite some significant advances in the field, the mechanisms by which HLA class I alleles mediate their beneficial or detrimental effects, are still unclear and may include multiple factors such as peptide binding, variability of targeted viral sequences, antigen processing and the kinetics of viral antigen expression. Recent data from murine studies have also linked T-cell receptor (TCR) repertoire diversity with relative control of viral infections. Comparing closely related MHC molecules presenting the identical epitope, these analyses revealed different TCR repertoire diversity depending on which MHC allele presented the targeted epitope and indicated that a narrow TCR repertoire was associated with CTL responses of low functional avidity and inability to control viral replication. Based on these recent reports and our own, extensive preliminary recent data, the present proposal aims to identify HIV encoded, promiscuously binding CTL epitopes that can be presented by HLA alleles differentially associated with HIV disease progression and to assess the functional avidity and TCR repertoire diversity of these CTL responses, depending on which allele the epitope is presented. Functional avidity and TCR repertoire diversity are then put in relation with the CTL's ability to efficiently recognize naturally occurring viral epitope variants and to drive viral evolution in response to immune selection pressure mediated by epitope presentation on alleles associated with wither fast or slow disease progression. Focusing on promiscuously binding CTL epitopes, the potential association between TCR repertoire diversity, functional avidity and rate of HIV disease progression can be assessed in the absence of a number of confounding effects that have limited similar analyses in the past. The emerging data will be of significant importance for HIV vaccine development and help the identification of true immune correlates of protective HIV immunity.

描述（由申请人提供）： HLA I 类限制性、HIV 衍生的 CTL 表位的混杂呈现 CTL 介导的细胞免疫被认为是宿主防御 HIV 感染的重要手段，并且许多 HLA I 类等位基因与缓慢或快速的 HIV 疾病进展有关。尽管该领域取得了一些重大进展，但 HLA I 类等位基因介导其有益或有害作用的机制仍不清楚，可能包括多种因素，如肽结合、目标病毒序列的变异性、抗原加工和病毒抗原表达的动力学。来自小鼠研究的最新数据也将 T 细胞受体 (TCR) 库多样性与病毒感染的相对控制联系起来。比较呈现相同表位的密切相关的 MHC 分子，这些分析揭示了不同的 TCR 库多样性，具体取决于哪个 MHC 等位基因呈现目标表位，并表明狭窄的 TCR 库与低功能亲合力和无法控制病毒复制的 CTL 反应相关。基于这些最近的报告和我们自己的大量初步数据，本提案旨在识别 HIV 编码的、混杂结合的 CTL 表位，这些表位可以由与 HIV 疾病进展差异相关的 HLA 等位基因呈现，并评估这些 CTL 反应的功能亲和力和 TCR 库多样性，具体取决于表位呈现的等位基因。然后，将功能亲和力和TCR库多样性与CTL有效识别天然存在的病毒表位变体并驱动病毒进化以响应由与快速或缓慢疾病进展相关的等位基因上的表位呈现介导的免疫选择压力的能力相关。着眼于混杂结合的 CTL 表位，TCR 库多样性、功能亲合力和 HIV 疾病进展速度之间的潜在关联可以在不存在许多混杂效应的情况下进行评估，这些混杂效应在过去限制了类似的分析。新出现的数据对于艾滋病毒疫苗的开发具有重要意义，并有助于识别保护性艾滋病毒免疫的真正免疫相关性。