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: 8500171
• 负责人: Sarah Elizabeth Palmer
• 金额: $ 40.89万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8500171
• 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.

在接受抑制治疗的HIV感染者中，确定HIV在哪里持续存在是至关重要的一步 朝着根除艾滋病毒的方向迈进。出于实际原因，对病毒库的研究主要集中在 外周血液的成分。然而，最近的发现表明，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来源、动态和性质 在一系列组织部位进行抑制治疗的患者中产生持续HIV感染的蓄水池。 研究小组将在T细胞亚群中确定艾滋病毒持久性/潜伏期的性质(幼稚、记忆、 中央记忆和效应/过渡性记忆)和来自小肠的造血祖细胞， 接受长期治疗(&gt；7年)的患者的大肠、淋巴结和骨髓 在急性和慢性感染期间进行治疗。我们还将研究罕见循环细胞中的艾滋病毒(这将是 从白细胞分离中获得)。将使用独特和创新的技术来(1)分析遗传 细胞亚群中HIV群体的组成，(2)量化细胞内HIV DNA和未剪接水平 RNA/剪接的RNA，并使用一种新的核酸化学来设计引物-探针，测量短流产 HIV转录本，(3)确定保留在不同细胞亚群中的HIV的复制能力， (4)揭示宿主细胞因素，这些因素决定哪些细胞可能藏匿或抵抗复制和/或潜伏的艾滋病毒和 (5)观察胶原沉积和纤维化对储集层大小和分布的影响。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……之外 了解艾滋病毒是如何在不同的细胞和组织中细分的，拟议的研究将提供 淋巴细胞宿主因子和淋巴组织结构变化对HIV支持作用的系统研究 潜伏期，并有助于确定病毒库的大小和性质。我们相信，这项研究将 提供前所未有的病毒总量的量化评估，我们的发现将 指导可减少和根除持久性艾滋病毒感染者的治疗干预措施。