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

• 批准号: 8991481
• 负责人: CHARLES R RINALDO
• 金额: $ 57.87万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 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/8991481
• 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; Health; 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; Reporting; Research; Resistance; T-Lymphocyte; Therapeutic; Tissues; Vaccines; Viral; Viral Load result; Virus Replication; antiretroviral therapy; base; exosome; men who have sex with men; novel; novel strategies; prevent; prophylactic; response; therapeutic vaccine; trait

 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。据推测，这是由于存在潜伏 HIV 感染的血液和组织 CD4+ T 细胞的长期储存库。在没有 cART 的情况下多年控制 HIV 疾病进展的一小部分 HIV 感染者统称为 NP（即非进展者），提供了病毒控制的“自然”模型以及治愈感染的线索 开发治疗性和预防性疫苗。 20 多年来，人们都知道专业抗原呈递细胞 (APC) 可以介导 CD4+ T 细胞中 HIV 的爆炸性复制，称为反式感染。然而，这种体外现象在艾滋病毒感染和疾病进展中的重要性尚不确定。我们最近报道，来自 NP 的 APC 缺乏转染 CD4+ T 细胞的能力。这种表型与这些 NP 的 APC 中独特的、增强的胆固醇代谢有关，并且它似乎是一种遗传特征。我们的中心假设是，来自 NP 的专业 APC 明显无法转染自体和异源 CD4+ T 细胞靶标，这是他们长期控制 HIV 感染的基础，这与 APC 内胆固醇代谢的改变有关。我们建议对胆固醇代谢改变的生物学和遗传基础进行深入分析，以防止 NP 中 HIV 转染，具体目标如下所述： 具体目标 1. 确认并扩展我们对广泛、明确定义的 NP 谱中缺乏 HIV 转染的生物学基础的理解。具体目标 2. 明确导致这些个体未发生反式感染的遗传和表观遗传因素。具体目标 3.分析HIV反式感染和NP的髓系和淋巴系APC中的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 R01 拨款，对这一现象有更多的了解，将对如何控制 HIV 疾病进展和开发 HIV 感染的功能性治疗方法产生重大的变革性影响。