Cholesterol-dependent control of HIV progression by antigen presenting cells

 描述（由申请方提供）：在cART存在下的病毒持续存在仍然是HIV感染的潜在功能性或根除性治愈的障碍。据推测，这是由于存在具有潜伏HIV感染的血液和组织CD 4 + T细胞的长期储存库。在没有cART的情况下控制HIV疾病进展多年的一小部分HIV感染者，统称为NP（即，无进展者），提供了一个“自然”的病毒控制模型和治愈感染的线索，以及 开发治疗性和预防性疫苗。20多年来，人们已经知道专职抗原呈递细胞（APC）可以介导CD 4 + T细胞中的爆炸性HIV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尚不确定。我们最近报道了来自NP的APC缺乏反式感染CD 4 + T细胞的能力。这种表型与这些NP的APC中胆固醇代谢的独特增强有关，并且它似乎是一种遗传性状。我们的中心假设是，来自NP的专业APC具有显著的不能反式感染自体和异源CD 4 + T细胞靶标的能力，这是其长期控制HIV感染的基础，并且这与其APC内胆固醇代谢的改变有关。我们建议深入分析胆固醇代谢改变的生物学和遗传学基础，以防止NP中的HIV反式感染，具体目标如下：具体目标1。确认并扩展我们对在广泛的、明确的NP谱中缺乏HIV反式感染的生物学基础的理解。具体目标2。定义遗传和表观遗传因素（S）负责这些人缺乏反式感染。具体目标 3.分析NP的骨髓和淋巴APC中的HIV反式感染和APC-T细胞通路，这是其缺乏反式感染的基础。我们相信，通过拟议的R 01赠款，对这一现象的更多了解将对如何控制艾滋病毒疾病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.