CNS Myeloid Cells as SIV Reservoirs: Persistent Infection and Rebound

CNS 骨髓细胞作为 SIV 储存库：持续感染和反弹

• 批准号: 10370645
• 负责人: Binhua Julie Ling
• 金额: $ 70.86万
• 依托单位: TEXAS BIOMEDICAL RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-04-01 至 2023-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10370645
• 关键词: AIDS/HIV problem; Address; Animal Model; Attention; Bar Codes; Biological Assay; Blood Circulation; Brain; Brain region; Cell Culture Techniques; Cells; Chinese People; Coin; Development; Effectiveness; Ensure; Ethical Issues; Fumarates; Genes; Genetic; Genome; Goals; HIV; HIV Infections; HIV-1; Human; Imaging Techniques; Infection; Interruption; Lead; Lung; Lymphocyte; Lymphoid Tissue; Macaca; Macaca mulatta; Measures; Microglia; Modeling; Molecular; Molecular Cloning; Molecular Virology; Myelogenous; Myeloid Cells; Neuroglia; Neurosciences; Organ; Patients; Phylogenetic Analysis; Plasma; Regimen; Research; Research Personnel; Role; SIV; Site; Source; Spleen; Statistical Data Interpretation; Structure of parenchyma of lung; System; T-Lymphocyte; Technology; Tenofovir; Tissues; Viral; Viral Load result; Viral reservoir; Viremia; Virus; Virus Diseases; Virus Replication; Work; antiretroviral therapy; base; brain tissue; chronic infection; emtricitabine; experience; glial activation; high throughput technology; in vivo; lymph nodes; macrophage; neuroAIDS; neuroimmunology; neuroinflammation; new technology; next generation sequencing; nonhuman primate; novel strategies; novel virus; peripheral blood; prevent; sample collection; simian human immunodeficiency virus; success; viral DNA; viral rebound; virology

Project Summary (Abstract) Preventing rebound of HIV following antiretroviral therapy interruption (ATI) remains a major problem. However, pinpointing the exact cells that serve as reservoirs from which the virus rebounds has proven elusive. An- tiretroviral therapy (ART) has shown effectiveness in removing productively infected cells from the periphery, with limited success in brain. However, once ART is withdrawn, virus rebounds, and infection in the brain coin- cide with neuroinvasion and concomitant neuroinflammation. The Long-Term Goal is to establish a basis for identifying and then preventing HIV rebounding upon ATI. The Objective of this Application is to develop a strategy for identifying, and a means of measuring, the myeloid reservoir in the CNS and other relevant organs. The Central Hypothesis is that infected microglia and other myeloid cells would be the source of rebounding virus following ATI. This is based on previous work from the interdisciplinary team of experience with ART and reservoir research in macaques (Ling), neuroimmunology (MacLean) and HIV-1/SIV molecular virology (Ling, Maness & Keele). We will employ a barcoded SIV (Keele), advanced imaging techniques, cell culture and next generation sequencing of the barcoded region to identify latently infected cells and determine which cells are the source of rebound virus upon ATI. Two Specific Aims are proposed: Specific Aim 1: Determine whether myeloid cells in CNS harbor reactivatable replication-competent virus in SIV-infected macaques under fully suppressive ART. While lymphocytes receive the most attention for HIV infection, myeloid cells in brain, lungs and lymphoid tissues are often overlooked as founder/ refounder target cells of HIV infection. Our hy- pothesis here is that SIV infected myeloid cells can be reactivated to produce infectious virus for new infection. Specific Aim 2: Determine whether myeloid cells in the CNS are a source of rebound virus upon ART interruption (ATI). We hypothesize that microglia and other myeloid cells would be the source of virus re- bound upon ATI. Our central hypothesis for this aim is that brain-specific barcodes and evolved sequences will be identified within myeloid cells following ATI and have high similarity with sequences isolated from rebound virus in peripheral blood. We believe once this project is completed, it will be possible to identify target cells to prevent HIV rebounding in the absence of continued ART. !

项目摘要（摘要） 预防抗逆转录病毒治疗中断（ATI）后艾滋病毒反弹仍然是一个主要问题。然而，在这方面， 精确定位作为病毒反弹宿主的细胞已被证明是难以捉摸的。安... 抗逆转录病毒疗法（ART）已经显示出从外周移除生产性感染细胞的有效性， 在大脑中的成功有限。然而，一旦停止抗逆转录病毒治疗，病毒就会反弹，大脑中的感染就会恶化- 有神经侵袭和伴随的神经炎症。长期目标是建立一个基础， 识别并预防艾滋病毒在ATI上反弹。本申请的目的是开发一个 用于识别CNS和其他相关器官中的骨髓储库的策略和测量方法。 中心假设是受感染的小胶质细胞和其他骨髓细胞将是反弹的来源 ATI之后的病毒。这是基于以前的工作，从跨学科团队的经验与艺术和 猕猴的储库研究（Ling）、神经免疫学（MacLean）和HIV-1/SIV分子病毒学（Ling， Maness & Keele）。我们将采用条形码SIV（基尔），先进的成像技术，细胞培养和下一步 对条形码化区域进行代测序，以鉴定潜伏感染的细胞并确定哪些细胞被感染。 ATI后反弹病毒的来源。具体目标1：确定是否 在SIV感染的猕猴中，CNS中的髓样细胞携带可再活化的复制能力病毒， 完全抑制性ART。虽然淋巴细胞受到HIV感染的最大关注，但脑中的髓样细胞， 肺和淋巴组织作为HIV感染的创始者/再创始者靶细胞常常被忽视。我们的hy- 这里的假设是SIV感染的骨髓细胞可以被重新激活以产生用于新感染的感染性病毒。 具体目标2：确定CNS中的髓样细胞是否是ART后反弹病毒的来源 中断（ATI）。我们假设小胶质细胞和其他髓样细胞是病毒再感染的来源。 在ATI上绑定。我们的中心假设是，大脑特异性条形码和进化序列将 在ATI后的髓样细胞内鉴定，并且与从反弹中分离的序列具有高度相似性 外周血中的病毒。我们相信，一旦这个项目完成，将有可能确定靶细胞， 在没有持续抗逆转录病毒治疗的情况下防止艾滋病毒反弹。 !