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.

确定接受抑制治疗的艾滋病毒感染者体内艾滋病毒持续存在的部位是至关重要的一步 走向消灭艾滋病毒。出于实际原因，病毒储存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 受感染细胞的比例。该项目的总体目标是确定 在接受抑制治疗的患者的一系列组织部位中产生持续性 HIV 感染的病毒库。 研究小组将确定 T 细胞亚群（幼稚细胞、记忆细胞、 中枢记忆和效应/过渡记忆）和来自小肠的造血祖细胞， 接受长期治疗（> 7 年）的患者的大肠、淋巴结和骨髓 急性和慢性感染期间的治疗。我们还将研究稀有循环细胞中的艾滋病毒（这将是 从白细胞分离术中获得）。将使用独特和创新的技术来（1）分析遗传 细胞亚群中 HIV 群体的构成，(2) 量化细胞内 HIV DNA 和未剪接的水平 RNA/剪接 RNA，并使用新型核酸化学进行引物探针设计，测量短的失败 HIV转录本，(3)确定不同细胞亚群中残留的HIV的复制能力， (4)揭示决定哪些细胞可能携带或抵抗复制和/或潜伏的HIV的宿主细胞因素 (5)考察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正在进行的补充工作（项目 4）。此外 了解艾滋病毒如何在不同细胞和组织之间细分，拟议的研究将提供一个 系统调查淋巴细胞宿主因子和淋巴结组织结构的变化如何支持艾滋病毒 潜伏期并有助于确定病毒库的规模和性质。我们相信这项研究将 对体内病毒储存量提供前所未有的定量评估，我们的研究结果将 指导可以减少和根除持续性艾滋病毒储存库的治疗干预措施。