HIV Pathogenesis and Immunity in Viremic Non-Progressors

描述（由申请人提供）：非常罕见的HIV-1感染者保持有效水平的CD4+ T细胞，并保持无症状，尽管持续的病毒载量大于104甚至105 HIV-1 RNA拷贝/ml血浆。这种对HIV-1感染的极不寻常的有利反应仍未完全描述。我们对三种这样的病毒血症非进展因子（VNP）的初步研究显示，尽管存在复制能力强的细胞病变R5 HIV-1，但缺乏非特异性免疫激活和一致的CD4+ T细胞对HIV-1的反应。因此，VNP模仿不发病的SIV自然宿主的免疫反应，包括黑白眉猴和非洲绿猴。详细了解这些罕见的个体如何在HIV-1高负荷情况下保持健康，将对了解HIV-1发病的正常过程和开发新的艾滋病治疗方法或疫苗非常有用。我们假设VNP表型是由复制能力强但细胞病变弱的HIV-1引起的，或者是由维持粘膜屏障并阻止非特异性免疫激活的有效免疫引起的。为了验证这一双重假设，我们有三个具体目标：1。从PBMC和胎儿胸腺器官培养的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以及HIV-1 QPCR来表征VNP PBMC亚群，以辨别HIV-1的免疫亚群或分布是否与其他HIV-1感染个体不同。检测免疫激活、血清LPS水平和可溶性CD14水平以及VNP新鲜PBMC与对照组相比的特异性HIV T细胞反应。

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.