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，HIV衍生的CTL表位CTL介导的细胞免疫的混杂表现被认为是宿主防御HIV感染的重要部门，并且许多HLA I类等位基因与缓慢或快速的HIV HIV疾病进展有关。尽管该领域有一些重大进展，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，例如肽结合，靶向病毒序列的变异性，抗原加工的变异性，抗原加工和病毒抗原表达的动力学。来自鼠研究的最新数据还将T细胞受体（TCR）曲目多样性与病毒感染的相对控制联系起来。这些分析比较了呈现相同表位的密切相关的MHC分子，这些分析表明，不同的TCR曲目多样性取决于MHC等位基因提出了靶向的表位，并表明狭窄的TCR库与低功能自行车的CTL反应有关，并且无法控制病毒复制。根据这些最新报告以及我们自己的广泛初步数据，目前的提案旨在识别与HLA等位基因相差与HIV疾病进展不同的HLA等位基因可以提出的艾滋病毒，与之结合的CTL表位，并评估这些CTL响应的功能性伴侣和TCR依赖性的多样性，这些ctl响应依赖于等等的eptepope，这些eptepe eptepope the Eptipe eptepope eptepope eptepope。然后将功能亲和力和TCR曲目多样性与CTL有效识别天然发生的病毒表位变体的能力相关，并驱动病毒进化，以响应于与wither快​​速或慢速疾病进展相关的等位基因上介导的免疫选择压力介导的免疫选择压力。在关注混合结合的CTL表位上，可以在没有多种混杂效应的情况下评估TCR库多样性，功能亲和力和HIV疾病进展率之间的潜在关联，而这些效应在过去限制了过去的类似分析。新兴数据对于艾滋病毒疫苗发育至关重要，并有助于鉴定保护性HIV免疫的真正免疫相关性。