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: 10390435
• 负责人: Binhua Julie Ling
• 金额: $ 69.87万
• 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 2024-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10390435
• 关键词: AIDS/HIV problem; Address; Animal Model; Attention; Bar Codes; Biological Assay; Blood Circulation; Brain; Brain region; Cell Culture Techniques; Cells; Chinese; 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 However, once ART is withdrawn, virus rebounds, and infection in the brain coin- cide with neuroinvasion and concomitant neuroinflammation.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. !

项目概要（摘要） 防止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， 事实证明，精确定位作为病毒反弹宿主的确切细胞是难以捉摸的。一个- 逆转录病毒疗法（ART）已显示出可有效去除外周有效感染的细胞， 在大脑方面取得的成功有限。然而，一旦停止抗逆转录病毒治疗，病毒就会反弹，大脑也会受到感染。 cide 伴有神经侵袭和伴随的神经炎症。长期目标是为以下目标奠定基础： 识别并预防 HIV 在 ATI 上反弹。该应用程序的目的是开发一个 识别中枢神经系统和其他相关器官中的骨髓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根源 ATI 之后的病毒。这是基于具有 ART 经验的跨学科团队之前的工作， 猕猴储存库研究 (Ling)、神经免疫学 (MacLean) 和 HIV-1/SIV 分子病毒学 (Ling, 马内斯和基尔）。我们将采用带条形码的 SIV (Keele)、先进的成像技术、细胞培养和下一步 对条形码区域进行世代测序，以识别潜伏感染的细胞并确定哪些细胞是 ATI反弹病毒的来源。提出了两个具体目标： 具体目标 1：确定是否 在 SIV 感染的猕猴中，中枢神经系统的骨髓细胞含有可重新激活的具有复制能力的病毒 完全抑制ART。虽然淋巴细胞在 HIV 感染中最受关注，但大脑中的骨髓细胞 肺和淋巴组织作为 HIV 感染的创建/重建靶细胞经常被忽视。我们的hy- 这里的假设是，SIV 感染的骨髓细胞可以重新激活，产生用于新感染的感染性病毒。 具体目标 2：确定中枢神经系统中的骨髓细胞是否是 ART 后反弹病毒的来源 中断（ATI）。我们假设小胶质细胞和其他骨髓细胞将是病毒重新传播的来源。 受 ATI 约束。我们对此目标的中心假设是，大脑特定的条形码和进化的序列将 在 ATI 后在骨髓细胞内被识别，并且与从反弹中分离出的序列具有高度相似性 外周血中存在病毒。我们相信，一旦该项目完成，将有可能识别出目标细胞 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。 ！