Cholesterol-dependent control of HIV progression by antigen presenting cells

 描述(由申请人提供)：病毒在CART存在的情况下持续存在，仍然是艾滋病毒感染的潜在功能或根除治疗的障碍。据推测，这是由于潜伏着HIV感染的血液和组织中存在长期的CD4+T细胞。一小部分HIV感染者在没有CART的情况下控制了HIV疾病的进展多年，统称为NP(即无进展者)，这为病毒控制提供了一种“自然”模式，也提供了治愈感染的线索 发展治疗性和预防性疫苗。20多年来，人们已经知道专业抗原提呈细胞(APC)可以在CD4+T细胞中介导HIV的爆炸性复制，称为反式感染。然而，这种体外现象在HIV感染和疾病进展中的重要性一直不确定。我们最近报道，NP来源的APC缺乏反式感染CD4+T细胞的能力。这种表型与这些NP的APC中一种独特的、增强的胆固醇代谢有关，这似乎是一种遗传特征。我们的中心假设是，来自NP的专业APC具有显著的反式感染自体和异种CD4+T细胞靶点的能力，这是他们长期控制HIV感染的基础，这与他们APC内胆固醇代谢的改变有关。我们建议对防止HIV在NP中反式感染的胆固醇代谢改变的生物学和遗传学基础进行深入的分析，具体目的如下：1.确认和扩展我们对在广泛的、明确定义的NP中缺乏HIV反式感染的生物学基础的理解。具体目的2.确定导致这些个体缺乏反式感染的遗传和表观遗传因素(S)。特定目标 3.分析NP的髓系和淋巴系APC中HIV的跨性感染和APC-T细胞途径，为其缺乏跨性感染奠定基础。我们相信，通过拟议的R01赠款更多地了解这一现象，将对如何控制艾滋病毒疾病的进展和开发艾滋病毒感染的功能性治疗方法产生重大的变革性影响。

 DESCRIPTION (provided by applicant): Viral persistence in the presence of cART continues to be the barrier to a potential functional or eradication cure of HIV infection. This is hypothesized to be due to the presence of a long-lived reservoir of blood and tissue CD4+ T cells with latent HIV infection. The small percentage of HIV-infected individuals who control HIV disease progression for many years without cART, collectively termed NP (i.e., nonprogressors), offer a "natural" model of viral control and clues to curing the infection as well as developing therapeutic and prophylactic vaccines. For over 20 years it has been known that professional antigen presenting cells (APC) can mediate explosive HIV replication in CD4+ T cells, termed trans infection. However, the importance of this in vitro phenomenon in HIV infection and disease progression has been uncertain. We have recently reported that APC from NP lack the ability to trans infect CD4+ T cells. This phenotype was related to a unique, enhanced metabolism of cholesterol in the APC of these NP and it appears to be a genetic trait. Our central hypothesis is that professional APC from NP have a remarkable inability to trans infect autologous and heterologous CD4+ T cell targets which underlies their long term control of HIV infection, and this is linked to altered cholesterol metabolism within their APC. We propose an in depth analysis of the biologic and genetic basis of the altered cholesterol metabolism that prevents HIV trans infection in NP as described in the following specific aims: Specific Aim 1. Confirm and extend our understanding of the biologic basis for the lack of HIV trans infection in a broad, well-defined spectrum of NP. Specific Aim 2. Define the genetic and epigenetic factor(s) responsible for the lack of trans infection in these individuals. Specific Aim 3. Analyze HIV trans infection and APC-T cell pathways in myeloid and lymphoid APC of NP that underlie their lack of trans infection. We believe that greater knowledge of this phenomenon through the proposed R01 grant will have a significant, transformative effect on how to control HIV disease progression and in developing a functional cure for HIV infection.