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: 8892978
• 负责人: Sarah Elizabeth Palmer
• 金额: $ 27.94万
• 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 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8892978
• 关键词: Acquired Immunodeficiency Syndrome; Acute; Affect; Anti-Retroviral Agents; Architecture; Blood; Bone Marrow; CD4 Positive T Lymphocytes; Cell Communication; 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; Histocompatibility Testing; Histologic; Human; Infection; Integration Host Factors; Intervention; Laboratories; Large Intestine; Latent Virus; Leukapheresis; Life; Lymph Node Tissue; Lymphoid; Lymphoid Cell; Lymphoid Tissue; Macaca; Measurement; Measures; Memory; Messenger RNA; MicroRNAs; Mind; Myelogenous; Myeloid Cells; Nature; Nucleic Acids; Pathologic; Patients; Pattern; Peripheral; Phenotype; Plasma; Population; Population Genetics; RNA; RNA Splicing; Relative (related person); Research; Research Infrastructure; Residual state; Rest; Role; Sampling; Site; Small Intestines; Source; Structure; Surveys; T-Lymphocyte; T-Lymphocyte Subsets; Techniques; Therapeutic; Tissues; Transcript; Viral; Viral Load result; Viremia; Virus; Work; antiretroviral therapy; base; cell type; collaboratory; deep sequencing; design; genetic makeup; innovation; lymph nodes; macrophage; memory CD4 T lymphocyte; new technology; nonhuman primate; novel; peripheral blood; promoter; purge; viral RNA

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.

确定抑制性治疗的艾滋病毒感染患者的艾滋病毒持续存在是至关重要的一步 迈向消除艾滋病毒。出于实际原因，病毒储层的研究主要集中在 外周血的成分。然而，最近的发现表明，组织部位具有很大的 感染细胞的比例。该项目的总体目标是确定的来源，动态和性质 在一系列组织部位的抑制治疗患者中产生持续的HIV感染的储层。 研究团队将确定T细胞子集中HIV持久性/潜伏期的性质（天真，记忆， 中央记忆和效应子/过渡记忆）和小肠的造血祖细胞， 长期治疗（> 7年）的大肠，淋巴结和骨髓 急性和慢性感染期间的治疗。我们还将研究罕见循环细胞中的HIV（这将是 从白细胞术获得）。独特而创新的技术将用于（1）分析遗传 细胞子集中的艾滋病毒群体的构成，（2）量化细胞内HIV DNA的水平和未贴合的水平 RNA/剪接的RNA，并使用新型的核酸化学进行引物设计，测量短流产 HIV转录本，（3）确定在不同细胞亚集中保留的HIV的复制能力， （4）揭示确定哪些细胞可能携带或抵抗复制和/或潜在艾滋病毒的宿主细胞因子，以及 （5）检查胶原蛋白沉积和纤维化对储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所做的互补工作（项目4）。此外 了解如何在不同细胞和组织之间细分HIV，拟议的研究将提供 系统调查淋巴样细胞宿主因素和淋巴结组织结构的变化如何支持HIV 延迟并帮助确定病毒储层的大小和性质。我们相信这项研究将 提供对病毒总体存储的前所未有的定量评估，我们的发现将 指导治疗干预措施，可以减少和根除持续的HIV储藏。