HLA-ALL IN THE CELLULAR IMMUNE RESPONSE TO HIV-1

描述(摘要)：预防艾滋病疫苗研究的一个主要目标 是为了确定预防HIV-1感染的免疫相关性。在……里面 在这种背景下，我们的建议试图理解人类白细胞抗原-A*1101(人类白细胞抗原-A11)、 在高度暴露的泰国队列中显著流行的I类MHC分子 持续血清阴性(HEPS)妓院工作人员，以及最常见的人类白细胞抗原-A 东南亚(SEA)的等位基因，与保护性有关的功能 对HIV-1感染的免疫力。我们的假设是，它可能与，至少在 这一类I等位基因与细胞毒性T淋巴细胞(CTL)的结合方式 表位并将其呈递给T细胞受体(TCR)。为了检验这一假设， 我们提出了人类白细胞抗原-A11复合体的生化和结晶学分析 与单一的HIV-1多肽结合。这些多肽将根据结果进行选择 来自我们对泰国人类白细胞抗原A11阳性HIV感染者和HEPS的CTL研究 个人。HIV-A11限制性表位在两者中的免疫优势 在这些捐赠者群体中，并在占主导地位的北美人之间 B分支和泰国主要分支HIV-1毒株将是 这些研究。由于CD8+CTL在初始免疫中起关键作用 人类白细胞抗原-A11复合体对HIV-1感染应答的分子特征 具有免疫优势的HIV-1多肽对于理解 这些队列中人类白细胞抗原-A11限制性CTL反应的性质。长期的 这项研究的目的是确定潜在的自然机制 增强对艾滋病毒-1感染的抵抗力，并为 能够复制这些表型的基于多肽的HIV-1疫苗的设计 免疫的保护性状态。从这些研究中获得的知识将 因此对艾滋病毒-1感染和其他传染性疾病有用 在海洋中流行的疾病，在那里这种等位基因非常常见。

DESCRIPTION (Abstract): A major goal of vaccine research for prevention of AIDS is to determine the immune correlates of protection against HIV-1 infection. In this context, our proposal seeks to understand how HLA-A*1101 (HLA-A11), a significantly prevalent class I MHC molecule in a cohort of Thai Highly Exposed Persistently Seronegative (HEPS) brothel workers, and the most common HLA-A locus allele in South East Asia (SEA), functions in relation to protective immunity to HIV-1 infection. Our hypothesis is that it may relate, at least in part, to the way this class I allele binds cytotoxic T lymphocyte (CTL) epitopes and presents them to T cell receptors (TCRs). To test this hypothesis, we propose a biochemical and crystallographic analysis of HLA-A11 complexed with single HIV-1 peptides. These peptides will be selected based on results from our CTL studies in Thai HLA-A11-positive HIV-infected and HEPS individuals. The HIV-A11-restricted epitopes which are immunodominant in both of these donor groups, and conserved between the predominant North American clade B and major Thai clade E strains of HIV-1, will be the initial focus of these studies. Since CD8+ CTLs play a critical role in the initial immune responses to HIV-1 infection, a molecular characterization of HLA-A11 complexed with immunodominant HIV-1 peptides is important and relevant to understand the nature of HLA-A11-restricted CTL responses in these cohorts. The long-term objective of this study is to identify natural mechanisms potentially able to confer resistance to HIV-1 infection and provide a structural framework for the design of peptide-based HIV-1 vaccines capable of reproducing these apparent protective states of immunity. Knowledge derived from these studies will therefore be useful in relation to HIV-1 infection and other infectious diseases prevalent in SEA where this allele is extremely common.