HIV Pathogenesis and Immunity in Viremic Non-Progressors

描述(由申请人提供)：非常罕见的HIV-1感染者保持有效的CD4T细胞水平，并保持无症状，尽管持续的病毒载量超过104甚至105个HIV-1RNA拷贝/毫升血浆。这种对HIV-1感染的极不寻常的、有利的反应仍然没有完全表现出来。我们最初对三种病毒型无进展病毒(VNP)的研究表明，尽管存在复制能力强、细胞病变的R5 HIV-1，但缺乏对HIV-1的非特异性免疫激活和一致的CD4T细胞反应。因此，VNP模拟了SIV自然宿主的免疫反应，这些宿主不会发展成疾病，包括红毛猴和非洲绿猴。对这些罕见的个体如何在HIV-1高负载的情况下保持健康的详细了解，将对了解HIV-1致病的正常过程以及开发新的艾滋病治疗或疫苗非常有用。我们假设VNP表型是由复制能力强但弱细胞病变的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。为了验证这一双重假设，我们有三个具体的目的：1.分离和鉴定来自VNP的HIV-1在PBMC和胎儿胸腺器官培养中的复制和细胞病变效应；2.通过免疫表型和细胞分选结合HIV-1 QPCR鉴定VNP的PBMC亚群，以区分HIV-1的免疫亚群或分布是否与其他HIV-1感染者不同；3.检测VNP与对照组的免疫激活、血清内毒素水平和可溶性CD14水平以及新鲜PBMC中HIV-1的特异性T细胞应答。 公共卫生相关性：病毒型非进展患者中的艾滋病毒致病机制和免疫非常罕见的艾滋病毒-1感染者保持有效的CD4T细胞水平，并保持无病状态，尽管病毒持续较高。这种对HIV-1感染的极不寻常的、有利的反应仍然没有完全表现出来。对这些罕见的个体如何在HIV-1高负载的情况下保持健康的详细了解，将对了解HIV-1致病的正常过程以及开发新的艾滋病治疗或疫苗非常有用。

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.