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 了解什么是自然感染中的保护性免疫;然后， 通过疫苗产生同样的保护性反应。测定 HIV感染中保护性免疫的相关性已被证明是难以捉摸的。 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 强有力的支持T辅助细胞，特别是细胞毒性T细胞的关键作用， 淋巴细胞（CTL）已经从HIV感染者的研究中出现， SIV感染的猕猴。这些最新的数据在很大程度上依赖于新的 可用的肽MHC四聚体试剂，以揭示密切的相互依赖性 CTL数量和控制HIV和SIV感染中的病毒血症。连同 Elispot分析，肽-MHC四聚体已经改变了 CTL应答，增加了检测的灵敏度和快速性， 大约50倍。然而，大多数工作既没有集中在 受全球流行病影响最大的人群，也不是C分支感染 在全球范围内占主导地位。目前的估计是， 艾滋病毒感染的全球负担主要在撒哈拉以南非洲。这就是 迫切需要开展针对疫苗的研究。理解CTL 预期可控制艾滋病毒感染的反应， 将被纳入候选疫苗，需要研究HLA I类 这些人群的分子特征，和精确的定义， 重要的C进化枝特异性CTL表位。这两个人口统计群体 受全球疫情影响最严重的是婴儿和年轻成年女性。 因此，这项建议具体侧重于建立一个 C进化枝感染的母亲从怀孕的目的是研究这些母亲 以及他们的孩子这些研究对象将 从南非德班的一家产前诊所招募， 目前血清阳性率为40- 50%。建议的具体目标 研究是a）确定CTL靶向的免疫显性C进化枝表位， 受该群体中普遍存在的HLA I类分子限制; B）比较 在感染的母亲和儿童中观察到对确定的表位的CTL应答， 为了确定CTL有效的情况， 控制病毒血症;和c）解决表位序列的相关性 疫苗设计的变化。