HIV-1 adaptation to HLA-restricted immune responses

HIV-1适应HLA限制性免疫反应

• 批准号: 6799159
• 负责人: SIMON Alexander MALLAL
• 金额: $ 25万
• 依托单位: MURDOCH UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-03-15 至 2009-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6799159
• 关键词: AIDS vaccines; T cell receptor; clinical research; cytotoxic T lymphocyte; drug resistance; enzyme linked immunosorbent assay; epitope mapping; flow cytometry; gene environment interaction; gene mutation; genetic polymorphism; helper T lymphocyte; histocompatibility antigens; host organism interaction; human immunodeficiency virus 1; human subject; immune response; microorganism immunology; natural selections; nucleic acid sequence; patient oriented research; population genetics; vaccine development; virus characteristic; virus genetics; virus load

DESCRIPTION (provided by applicant): HIV-1 has a remarkable capacity to adapt to individual human hosts by escaping cytotoxic T lymphocyte (CTL) responses mediated by human leukocyte antigen (HLA) recognition. Though HLA types are highly polymorphic, and there is site-specific functional constraint to change in the virus, HIV-1 appears to escape HLA-restricted CTL (and possibly CD4 T helper cell) responses by genetic mutation. Here, the study of HLA-driven adaptation at a population level will be used to understand determinants of HIV-1 disease severity in the HIV-1 infected individual and to guide design of a vaccine that would most effectively overcome the adaptability of HIV-1 in human populations. The specific aims are to: 1) Characterize HIV-1 adaptation to HLA at a (host) population level to identify immune escape/adaptations across full length HIV-1 sequences in a large drug-naive cohort that has HLA and viral diversity representative of populations in the US; 2) Correlate HLA-driven adaptation to viral load; 3) Determine immunological and virological determinants of HLA-driven adaptation and viral load. The sites of HLA-associated selection will mark out in vivo epitope targets of immune responses and the viral load effects of escape at these sites serve as a quantitative measure of the balance between host immune pressure and genetic barrier to mutation unique to every specific escape/adaptation. The information will be used to (i) correlate in-vivo HLA class I selection effects with assayed ex-vivo CTL responses (ii) define novel CTL and CD4 T helper epitopes (ii) measure magnitude, phenotype and T cell receptor (TCR) characteristics of T cells that favour or mitigate specific adaptations and (iii) measure the replicative fitness cost that constrains immune selection at these sites; 4) Design a 'population-optimised' HIV-1 vaccine. The results will be used to determine how well the immune responses induced by a given vaccine would recognise diverse, variably HLA-adapted HIV-1 strains at those epitopes most critical for the prevalent HLA types of the study cohort.

描述（由申请人提供）：HIV-1 通过逃避由人类白细胞抗原 (HLA) 识别介导的细胞毒性 T 淋巴细胞 (CTL) 反应，具有显着的适应个体人类宿主的能力。尽管 HLA 类型具有高度多态性，并且病毒的变化存在位点特异性功能限制，但 HIV-1 似乎可以通过基因突变逃避 HLA 限制的 CTL（可能还有 CD4 T 辅助细胞）反应。在这里，对人群水平上 HLA 驱动的适应性的研究将用于了解 HIV-1 感染者中 HIV-1 疾病严重程度的决定因素，并指导设计最有效地克服 HIV-1 适应性的疫苗在人群中。具体目标是： 1) 在（宿主）人群水平表征 HIV-1 对 HLA 的适应，以识别大型未曾药物队列中全长 HIV-1 序列的免疫逃逸/适应，该队列具有 HLA 和病毒多样性代表美国人口； 2）将HLA驱动的适应与病毒载量相关联； 3) 确定 HLA 驱动的适应和病毒载量的免疫学和病毒学决定因素。 HLA相关选择的位点将标出免疫反应的体内表位靶点，并且这些位点的逃逸病毒载量效应可作为宿主免疫压力和每个特定逃逸所特有的突变遗传屏障之间平衡的定量测量。适应。这些信息将用于 (i) 将体内 HLA I 类选择效应与测定的体外 CTL 反应关联起来 (ii) 定义新的 CTL 和 CD4 T 辅助表位 (ii) 测量强度、表型和 T 细胞受体 (TCR)有利于或减轻特定适应的 T 细胞特征，以及 (iii) 测量限制这些位点免疫选择的复制适应性成本； 4) 设计一种“针对人群优化的”HIV-1 疫苗。结果将用于确定给定疫苗诱导的免疫反应对不同的、不同的 HLA 适应性 HIV-1 毒株的识别能力，这些毒株的表位对于研究队列中普遍存在的 HLA 类型最为关键。