Viral reservoirs and sanctuaries in HAART - treated patients: role and mechanisms

HAART 治疗患者中的病毒库和庇护所：作用和机制

• 批准号: 8202570
• 负责人: Sarah Elizabeth Palmer
• 金额: $ 45.13万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-08 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8202570
• 关键词: Acquired Immunodeficiency Syndrome; Acute; Anti-Retroviral Agents; Blood; Bone Marrow; CD4 Positive T Lymphocytes; Cells; Chemistry; Chronic; Collagen; Competence; Complement; DNA; Deposition; Fibrosis; Future; Genetic; Genetic Transcription; Goals; Gut associated lymphoid tissue; HIV; HIV Infections; HIV therapy; Hematopoietic and Lymphoid Tissue; Hematopoietic stem cells; Highly Active Antiretroviral Therapy; Infection; Integration Host Factors; Intervention; Laboratories; Large Intestine; Leukapheresis; Life; Lymph Node Tissue; Lymphoid Cell; Lymphoid Tissue; Macaca; Measurement; Measures; Memory; Mind; Nature; Nucleic Acids; Patients; Pattern; Peripheral; Phenotype; Plasma; Population; Population Genetics; RNA; RNA Splicing; Relative (related person); Research; Residual state; Rest; Role; Sampling; Site; Small Intestines; Source; Structure; Surveys; T-Lymphocyte Subsets; Techniques; Tissues; Transcript; Viral; Viral Load result; Viremia; Virus; Work; antiretroviral therapy; base; cell type; design; genetic analysis; innovation; lymph nodes; macrophage; memory CD4 T lymphocyte; new technology; nonhuman primate; novel; peripheral blood

Identifying where HIV persists in HIV-infected patients on suppressive therapy is a critically important step towards HIV eradication. For practical reasons, the study of viral reservoirs has largely focused on components of peripheral blood. Recent findings, however, show that tissue sites harbor a substantial proportion of infected cells. The overall goal of this Project is to identify the source, dynamics, and nature of the reservoir producing persistent HIV infection in patients on suppressive therapy in a range of tissue sites. The research team will determine the nature of HIV persistence/latency in T-cell subsets (naive, memory, central memory and effector/transitional memory) and hematopoietic progenitor cells from the small bowel, large bowel, lymph nodes, and bone marrow of patients on long-term therapy (>7 years) who initiated therapy during acute and chronic infection. We will also investigate HIV in rare circulating cells (which will be obtained from leukapheresis). Unique and innovative techniques will be used to (1) analyze the genetic make-up of HIV populations in the cell subsets, (2) quantify the levels of intracellular HIV DNA and unspliced RNA/spliced RNA and, using a novel nucleic acid chemistry for primer-probe design, measure short abortive HIV transcripts, (3) determine the replication competence of the HIV remaining in different cellular subsets, (4) reveal host cell factors that determine which cells may harbor or resist replicating and/or latent HIV and (5) examine the effect of collagen deposition and fibrosis on the size and distribution of the reservoirs. We will also support complementary work being done in tissue-based macrophages (Project 4). In addition to understanding how HIV is subdivided among different cells and tissues, the proposed study will provide a systematic survey of how lymphoid cell host factors and changes in lymph node tissue structure support HIV latency and help determine the magnitude and nature of the viral reservoirs. We believe that this study will provide an unprecedented quantitative assessment of total body stores of virus and that our findings will guide treatment interventions that can reduce and eradicate persistent HIV reservoirs.

确定艾滋病毒在接受抑制治疗的艾滋病毒感染患者中的持续存在是至关重要的一步 致力于根除艾滋病由于实际原因，病毒储库的研究主要集中在 外周血的成分。然而，最近的研究结果表明，组织部位含有大量的 感染细胞的比例。本项目的总体目标是确定的来源，动力学，和性质 在一系列组织部位的抑制治疗中，储存库产生持续的HIV感染。 研究小组将确定艾滋病毒在T细胞亚群（幼稚，记忆， 中枢记忆和效应/过渡记忆）和来自小肠的造血祖细胞， 大肠、淋巴结和骨髓的长期治疗（>7年）患者， 治疗急性和慢性感染。我们还将研究罕见的循环细胞中的艾滋病毒（这将是 从白细胞分离术中获得）。独特和创新的技术将用于（1）分析基因 细胞亚群中HIV群体的组成，（2）定量细胞内HIV DNA和未剪接的水平， RNA/剪接的RNA，并使用一种新的核酸化学引物探针设计，测量短败育 HIV转录本，（3）决定HIV在不同细胞亚群中的复制能力， (4)揭示宿主细胞因子，其决定哪些细胞可能窝藏或抵抗复制和/或潜伏的HIV， (5)检查胶原沉积和纤维化对储库大小和分布的影响。我们 还将支持在基于组织的巨噬细胞中进行的补充工作（项目4）。除了 了解艾滋病毒是如何在不同的细胞和组织中细分的，这项拟议的研究将提供一个 淋巴细胞宿主因子和淋巴结组织结构变化如何支持HIV的系统调查 潜伏期和帮助确定病毒库的大小和性质。我们相信这项研究将 提供了一个前所未有的定量评估的总身体储存的病毒，我们的研究结果将 指导治疗干预措施，以减少和根除持续存在的艾滋病毒宿主。