Cholesterol-dependent control of HIV progression by antigen presenting cells

抗原呈递细胞对 HIV 进展的胆固醇依赖性控制

基本信息

批准号：
8921604
负责人：
CHARLES R RINALDO
金额：
$ 54.82万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-01-01 至 2019-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8921604
关键词：
Acquired Immunodeficiency Syndrome Antigen-Presenting Cells Applications Grants Archives Autologous B-Lymphocytes Blood CD4 Positive T Lymphocytes Cell membrane Cholesterol Cholesterol Homeostasis Cohort Studies Cytotoxic T-Lymphocytes Dendritic Cells Disease Progression Epigenetic Process Exhibits Genes Genetic Grant HIV HIV Infections Immunologics In Vitro Individual Infection Knowledge Lead Life Link Lymphoid Mediating Metabolic Pathway Modeling Mutation Myelogenous Pathway interactions Peripheral Blood Mononuclear Cell Pharmacotherapy Phenotype Plasma RNA Relative (related person)Reporting Research Resistance T-Lymphocyte Therapeutic Tissues Vaccines Viral Viral Load result Virus Replication antiretroviral therapy base men who have sex with men novel novel strategies prevent prophylactic public health relevance response therapeutic vaccine trait

项目摘要

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.

描述（由申请人提供）：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，这是由于存在长期的血液和组织储存库。具有潜伏性 HIV 感染的 CD4+ T 细胞，在没有 cART 的情况下多年控制 HIV 疾病进展的一小部分人，统称为 NP（即非进展者），提供了一种“自然”模型。病毒控制和治愈感染的线索 20 多年来，人们已经知道专业抗原呈递细胞 (APC) 可以介导 CD4+ T 细胞中的 HIV 爆炸性复制，称为反式感染，这种体外现象在 HIV 感染和疾病进展中的重要性。我们最近报道，来自 NP 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 中胆固醇代谢的独特性有关，并且它似乎是一种遗传因素。我们的中心假设是，来自 NP 的专业 APC 明显无法感染自体和异源 CD4+ T 细胞靶标，这是其长期控制 HIV 感染的基础，这与 APC 内胆固醇代谢的改变有关。深入分析胆固醇代谢改变的生物学和遗传基础，以防止 NP 中 HIV 转染，具体目标如下所述：具体目标 1. 确认并扩展我们对缺乏 HIV 转染的生物学基础的理解广泛、明确的 NP 范围。具体目标 2. 确定导致这些个体不存在反式感染的遗传和表观遗传因素。 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。控制艾滋病毒疾病进展并开发有效治疗艾滋病毒感染的方法。