HIV Pathogenesis and Immunity in Viremic Non-Progressors

描述（由申请人提供）：尽管病毒载量持续高于 104 甚至 105 HIV-1 RNA 拷贝/ml 血浆，但极少数 HIV-1 感染者仍保留有效水平的 CD4 T 细胞并且保持无症状。这种对 HIV-1 感染的极其不寻常的有利反应仍未完全表征。我们对三种病毒血症非进展细胞 (VNP) 的初步研究表明，尽管存在复制能力、细胞病变的 R5 HIV-1，但缺乏非特异性免疫激活和对 HIV-1 的一致 CD4 T 细胞反应。因此，VNP 模仿了不发病的 SIV 自然宿主的免疫反应，包括白眉猴和非洲绿猴。详细了解这些稀有个体如何在 HIV-1 载量较高的情况下保持健康，对于了解 HIV-1 发病机制的正常过程以及开发艾滋病新疗法或疫苗非常有用。我们假设 VNP 表型是由具有复制能力但细胞病变性较弱的 HIV-1 引起的，或者是由维持粘膜屏障并防止非特异性免疫激活的有效免疫引起的。为了检验这一双重假设，我们有三个具体目标：1. 分离并表征 PBMC 和胎儿胸腺器官培养物中 VNP 的 HIV-1 复制和细胞病变效应，2. 通过免疫表型分析和细胞分选加上 HIV-1 QPCR 来表征 VNP PBMC 子集，以辨别免疫子集或 HIV-1 的分布是否与其他 HIV-1 感染个体不同，3. 测定免疫激活、血清 LPS 水平和可溶性 CD14 水平：以及与对照相比，来自 VNP 的新鲜 PBMC 中的特异性 HIV T 细胞反应。 公共卫生相关性：病毒血症非进展者中的 HIV 发病机制和免疫 非常罕见的 HIV-1 感染者保留有效水平的 CD4 T 细胞，并且尽管病毒持续处于高水平，但仍保持无病状态。这种对 HIV-1 感染的极其不寻常的有利反应仍未完全表征。详细了解这些稀有个体如何在 HIV-1 载量较高的情况下保持健康，对于了解 HIV-1 发病机制的正常过程以及开发艾滋病新疗法或疫苗非常有用。

DESCRIPTION (provided by applicant): Very rare HIV-1 infected individuals retain effective levels of CD4+ T cells and remain asymptomatic despite consistent viral loads greater than 104 or even 105 HIV-1 RNA copies/ml plasma. This extremely unusual, favorable response to HIV-1 infection remains incompletely characterized. Our initial study of three such viremic non-progressors (VNP) showed a lack of non-specific immune activation and consistent CD4+ T cell responses to HIV-1 despite the presence of replication competent, cytopathic R5 HIV-1. VNP therefore mimic the immune response of natural hosts of SIV that do not develop disease, including the sootey mangabey and African green monkey. Developing a detailed understanding of how these rare individuals remain healthy despite high HIV-1 load will be extremely useful in understanding the normal process of HIV-1 pathogenesis and in developing new treatments or vaccines for AIDS. We hypothesize that the VNP phenotype is caused by replication competent but weakly cytopathic HIV-1 or by effective immunity that maintains the mucosal barrier and prevents non-specific immune activation. To test this dual hypothesis we have three specific aims: 1. Isolate and characterize the replication and cytopathic effects of HIV-1 from VNP in PBMC and fetal thymic organ culture, 2. Characterize VNP PBMC subsets by immunophenotyping and cell sorting plus HIV-1 QPCR to discern whether immune subsets or the distribution of HIV-1 differ from other HIV-1 infected individuals, 3. Assay immune activation, serum LPS levels and soluble CD14 levels as well as specific HIV T cell responses in fresh PBMC from VNP compared with controls. PUBLIC HEALTH RELEVANCE: HIV Pathogenesis and Immunity in Viremic Non-Progressors Very rare HIV-1 infected individuals retain effective levels of CD4+ T cells and remain disease free despite consistent high viral. This extremely unusual, favorable response to HIV-1 infection remains incompletely characterized. Developing a detailed understanding of how these rare individuals remain healthy despite high HIV-1 load will be extremely useful in understanding the normal process of HIV-1 pathogenesis and in developing new treatments or vaccines for AIDS.