CTL-MEDIATED CONTROL--PEDIATRIC/ADULT C-CLADE INFECTION

CTL 介导的控制——儿童/成人 C 分支感染

• 批准号: 6374422
• 负责人: PHILIP J GOULDER
• 金额: $ 57.13万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-09-15 至 2005-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6374422
• 关键词: AIDS vaccines; Africa; HIV infections; MHC class I antigen; cellular immunity; clinical research; communicable disease control; cytotoxic T lymphocyte; epidemiology; genetic strain; human pregnant subject; human subject; mother /infant health care; pediatric AIDS; vaccine development; virus antigen; virus load

A rational approach to vaccine design would be, first, to understand what constitutes protective immunity in natural infection; then, to generate the same protective responses by means of vaccine. Determination of the correlates of protective immunity in HIV infection has proved elusive. However, data have accumulated over the past decade, which point to the importance of anti-HIV cellular immunity in this regard. More recently, very strong support for the critical role of T helper and, especially, cytotoxic T lymphocytes (CTL) has emerged from work both on HIV-infected humans and SIV-infected macaques. These recent data have leant heavily upon newly available peptide MHC tetrameric reagents to reveal the close interdependence of CTL numbers and control of viremia in HIV and SIV infection. Together with Elispot assays, the peptide-MHC tetramers have transformed the scope of work on CTL responses , increasing the sensitivity and the rapidity of the assays each approximately 50-fold. Most work, however, has neither focused upon the populations most affected by the global epidemic, nor upon C clade infection which predominates worldwide. Current estimates are that two-thirds of the global burden of HIV infection is borne in sub-Saharan Africa. This is where vaccine-directed research urgently needs to be applied. Understanding the CTL responses which can be expected to exert control of HIV infection, and which would be incorporated into candidate vaccine, requires study of the HLA class I molecules characteristic of these populations, and precise definition of the important C clade-specific CTL epitopes. The two demographic groups most critically affected by the global epidemic are infants and young adult females. This proposal therefore specifically concentrates upon establishing a cohort of C clade infected mothers from pregnancy with the aim of studying these mothers and their children from childbirth onwards. These study subjects will be recruited from an antenatal clinic in Durban, South Africa, where the HIV seroprevalence is presently 40-50 percent. The specific aims of the proposed study are a) to define the immunodominant C clade epitopes targeted by CTL, restricted by HLA class I molecules prevalent in this population; b) to compare CTL responses observed in infected mothers and children to defined epitopes, with the purpose of determining the circumstances in which CTL are effective in controlling viremia; and c) to address the relevance of epitope sequence variation to vaccine design.

疫苗设计的合理方法首先是 了解自然感染中保护性免疫的构成是什么；那么，到 通过疫苗产生相同的保护反应。测定 事实证明，艾滋病毒感染中保护性免疫的相关性难以捉摸。 然而，过去十年积累的数据表明 抗HIV细胞免疫在这方面的重要性。最近，非常 强烈支持 T 辅助细胞，特别是细胞毒性 T 的关键作用 淋巴细胞（CTL）是从艾滋病毒感染者和艾滋病毒感染者的研究中出现的。 感染 SIV 的猕猴。这些最近的数据很大程度上依赖于新的 可用肽 MHC 四聚体试剂揭示紧密的相互依赖性 HIV 和 SIV 感染中 CTL 数量和病毒血症的控制。连同 Elispot 检测，肽-MHC 四聚体改变了研究的工作范围 CTL反应，提高了检测的灵敏度和速度 大约50倍。然而，大多数工作都没有关注 受全球流行病影响最严重的人群，也不是受 C 分支感染影响最严重的人群 在世界范围内占主导地位。目前的估计是三分之二 全球艾滋病毒感染负担由撒哈拉以南非洲承担。这是哪里 疫苗导向的研究迫切需要得到应用。了解 CTL 预计可以控制艾滋病毒感染的反应，以及 将纳入候选疫苗，需要研究 HLA I 类 这些群体的分子特征，以及精确的定义 重要的 C 进化枝特异性 CTL 表位。这两个人口群体最 受全球流行病影响严重的是婴儿和年轻成年女性。 因此，该提案特别侧重于建立一批 C分支从怀孕期间感染母亲，目的是研究这些母亲 以及他们的孩子从分娩开始。这些研究课题将是 招募自南非德班的一家产前诊所，那里的艾滋病毒 目前血清流行率为 40-50%。拟议的具体目标 研究内容 a) 定义 CTL 靶向的免疫显性 C 进化枝表位， 受到该人群中普遍存在的 HLA I 类分子的限制； b) 比较 在受感染的母亲和儿童中观察到的 CTL 对特定表位的反应， 目的是确定 CTL 在何种情况下有效 控制病毒血症； c) 解决表位序列的相关性 疫苗设计的变化。