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（由适用提供）：在货车存在下的病毒持久性仍然是HIV感染潜在功能或放射性治疗的障碍。假设这是由于存在带有潜在HIV感染的血液和组织CD4+ T细胞的长寿命库。多年来控制HIV疾病进展多年的艾滋病毒感染的个体的少数没有卡车，共同称为NP（即非推测者），为病毒控制和线索提供了“自然”模型，也提供了治疗感染的线索作为发展治疗和预防性疫苗。 20多年来，众所周知，专业的抗原呈递细胞（APC）可以在CD4+ T细胞中的爆炸性HIV复制，称为翻译感染。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。我们最近报告说，NP的APC缺乏转移感染CD4+ T细胞的能力。该表型与这些NP APC中胆固醇的独特，增强的代谢有关，并且似乎是一种遗传特征。我们的中心假设是，来自NP的专业APC具有显着的无法转化自体和异源CD4+ T细胞靶标，这是其对HIV感染的长期控制的基础，这与APC中胆固醇代谢的改变有关。我们对改变的胆固醇代谢的生物学和遗传基础进行了深入分析，如以下特定目的：特定目的1。确认并扩展了我们对NP宽，良好，良好的NP光谱中缺乏HIV跨感染的生物学基础的NP中HIV反式感染的理解。具体目的2。定义负责这些个体缺乏跨性别感染的遗传和表观遗传因素。具体目标 3。分析NP的髓样和淋巴APC中的HIV转染和APC-T细胞途径，这是它们缺乏转染的基础。我们认为，通过拟议的R01赠款对这一现象的了解更大，将对如何控制HIV疾病进展以及为HIV感染开发功能性治疗产生重大的变革作用。