HIV Pathogenesis and Immunity in Viremic Non-Progressors

描述（由申请方提供）：非常罕见的HIV-1感染者保留有效水平的CD 4 + T细胞，尽管病毒载量持续大于104甚至105 HIV-1 RNA拷贝/ml血浆，但仍无症状。这种对HIV-1感染的极不寻常的有利反应仍然没有完全表征。我们对三个这样的病毒血症非进展者（VNP）的初步研究显示，尽管存在有复制能力的致细胞病变的R5 HIV-1，但缺乏非特异性免疫激活和对HIV-1的一致的CD 4 + T细胞应答。因此，VNP模拟SIV的天然宿主的免疫反应，这些宿主不发生疾病，包括白眉猴和非洲绿色猴。详细了解这些罕见的个体如何在高HIV-1载量的情况下保持健康，对于理解HIV-1发病机制的正常过程和开发艾滋病的新疗法或疫苗将非常有用。我们推测，VNP表型是由复制能力，但弱致细胞病变的HIV-1或有效的免疫，维持粘膜屏障，防止非特异性免疫激活。为了检验这一双重假设，我们有三个具体目标：1。在PBMC和胎儿胸腺器官培养中从VNP中分离并表征HIV-1的复制和细胞病变效应。通过免疫表型和细胞分选加上HIV-1 QPCR表征VNP PBMC亚群，以辨别免疫亚群或HIV-1的分布是否与其他HIV-1感染个体不同，3.检测VNP与对照组新鲜PBMC中的免疫活化、血清LPS水平和可溶性CD 14水平以及特异性HIV T细胞应答。 公共卫生相关性：病毒血症非进展者中的HIV发病机制和免疫性非常罕见的HIV-1感染者保留有效水平的CD 4 + T细胞，尽管持续的高病毒感染率，但仍保持无病状态。这种对HIV-1感染的极不寻常的有利反应仍然没有完全表征。详细了解这些罕见的个体如何在高HIV-1载量的情况下保持健康，对于理解HIV-1发病机制的正常过程和开发艾滋病的新疗法或疫苗将非常有用。

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.