Mechanisms of CMV Replication on HIV Persistence

CMV 复制对 HIV 持续存在的机制

基本信息

批准号：
10448351
负责人：
Sara Gianella Weibel
金额：
$ 82.32万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-08-19 至 2025-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10448351
关键词：
AIDS clinical trial group Affect Antigens Biological Assay Biological Markers Blood specimen Bystander Effect CCR5 gene CD4 Positive T Lymphocytes CD8B1 gene Cells Chronic Clinical Trials Clonal Expansion Clonality Complement Cytomegalovirus Cytomegalovirus Infections DNA DNA Integration Data Enzyme-Linked Immunosorbent Assay Event Flow Cytometry Frequencies Funding Future Gene Expression Genes Genomic DNA Granzyme HIV HLA-DR Antigens Health Human Human Herpesvirus 4 Immune Immune System Diseases Immune response Immune system Immunologics Impairment Individual Inflammation Inflammatory Influenza Interleukin-1 beta Interleukin-10 Interleukin-6 Investments Knowledge Leukapheresis Measures Methods Modernization Morbidity - disease rate Mucous Membrane Natural Killer Cells Participant Pathway interactions Peripheral Blood Mononuclear Cell Persons Pharmaceutical Preparations Placebos Plasma Play Proviruses RNA Research Research Design Role Sampling T cell receptor repertoire sequencing T-Lymphocyte TNF gene TRIM Gene Testing Time United States National Institutes of Health Variant Viral Viral Antigens Virus Virus Activation Virus Replication antiretroviral therapy co-infection design exhaust immune checkpoint in vivo integration site memory CD4 T lymphocyte monocyte novel pathogen perforin prevent programmed cell death protein 1 randomized placebo controlled trial single-cell RNA sequencing success systemic inflammatory response

项目摘要

Modified Project Summary/Abstract Section HIV cure efforts will likely continue to be futile if we ignore the inflammatory mechanisms sustaining the persistence of HIV. Scientific Premise: A common driver of inflammation for persons with HIV (PWH) is Cytomegalovirus (CMV), which almost universally co-infects PWH. During this coinfection, subclinical CMV replication is frequent and profoundly impacts the immune system, including several CMV-driven mechanisms that promote HIV persistence, even during antiretroviral therapy (ART). Some of these mechanisms could skew the HIV provirus towards preferentially integrating into CMV specific CD4+ T cells. Also, as CMV specific CD4+ T cells comprise a large proportion of all CD4+ T cells, so understanding how they contribute to HIV persistence would be essential for HIV cure efforts. Strengths of the proposed research are that it will use state-of-the-art methods and will leverage prior NIH-investments to collect appropriate biospecimens and data as part of an ACTG-funded, randomized trial of the anti-CMV drug letermovir (A5383, Co-chairs: Gianella, Hunt) as well as anti-CMV vaccine Triplex (A5355, Chair: Sara Gianella). Study Design: Our project is designed to carefully and rigorously elucidate the CMV-driven mechanisms that impact HIV persistence. Aim 1 will determine how various viral antigens (CMV, Influenza, EBV and HIV) directly induce clonal expansion of HIV-infected CD4+ T cells ex vivo. Aim 2 will assess the indirect effect of suppressing CMV with letermovir or vaccine on HIV reservoirs and T cell repertoire in vivo. To clarify mechanistic pathways of ex vivo and in vivo observations in Aims 1 and 2, we will characterize specific immunologic mechanisms associated with clonal expansion and inflammation in association with CMV and HIV persistence. Overall Objective: HIV cure efforts will likely be futile if we ignore the inflammatory mechanisms that sustain the HIV reservoir. This project is in line with NIH OAR priorities because it will assess the mechanisms by which viral antigens (CMV, EBV, Influenza and HIV) influence HIV persistence through expansion of CD4+ T cells that carry HIV DNA (Aim 1). Further, we will determine the benefits of suppressing CMV to decrease immune dysfunction and HIV cell reservoirs (Aims 2 and 3). Impact: The proposed project will have meaningful impact by determining how suppressing CMV with letermovir may influence inflammation, immune dysfunction, and HIV reservoirs. Generated results will advance both the HIV cure and PWH health agendas.

修改后的项目摘要/摘要部分如果我们忽视维持艾滋病毒持续存在的炎症机制，艾滋病毒治疗努力可能会继续徒劳。科学前提：引起 HIV 感染者 (PWH) 炎症的常见驱动因素是巨细胞病毒 (CMV)，它几乎普遍同时感染 PWH。在这种合并感染过程中，亚临床 CMV 复制很频繁，并对免疫系统产生深远影响，包括几种 CMV 驱动的机制，即使在抗逆转录病毒治疗 (ART) 期间，也会促进 HIV 持续存在。其中一些机制可能会使 HIV 原病毒优先整合到 CMV 特异性 CD4+ T 细胞中。此外，由于 CMV 特异性 CD4+ T 细胞占所有 CD4+ T 细胞的很大一部分，因此了解它们如何促进 HIV 持续存在对于 HIV 治疗工作至关重要。拟议研究的优势在于，它将使用最先进的方法，并利用 NIH 之前的投资来收集适当的生物样本和数据，作为 ACTG 资助的抗 CMV 药物莱特莫韦 (letermovir) 随机试验的一部分 (A5383 ，联合主席：Gianella、Hunt）以及抗 CMV 疫苗 Triplex（A5355，主席：Sara Gianella）。研究设计：我们的项目旨在仔细、严格地阐明影响 HIV 持久性的 CMV 驱动机制。目标 1 将确定各种病毒抗原（CMV、流感、EBV 和 HIV）如何直接诱导 HIV 感染的 CD4+ T 细胞离体克隆扩增。目标 2 将评估用莱特莫韦或疫苗抑制 CMV 对体内 HIV 储存库和 T 细胞库的间接影响。为了阐明目标 1 和 2 中离体和体内观察的机制途径，我们将描述与 CMV 和 HIV 持久性相关的克隆扩张和炎症相关的特定免疫机制。总体目标：如果我们忽视维持艾滋病毒储存库的炎症机制，艾滋病毒治疗努力可能是徒劳的。该项目符合 NIH OAR 的优先事项，因为它将评估病毒抗原（CMV、EBV、流感和 HIV）通过扩增携带 HIV DNA 的 CD4+ T 细胞影响 HIV 持久性的机制（目标 1）。此外，我们将确定抑制 CMV 对减少免疫功能障碍和减少 HIV 细胞储存的益处（目标 2 和 3）。影响：拟议的项目将通过确定莱特莫韦抑制 CMV 如何影响炎症、免疫功能障碍和 HIV 储存库而产生有意义的影响。产生的结果将推动艾滋病毒治疗和艾滋病毒感染者健康议程。