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：
10241944
负责人：
Sara Gianella Weibel
金额：
$ 80.16万
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 2024-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10241944
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

Abstract 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 placebo- controlled trial of the anti-CMV drug letermovir (A5383, Co-chairs: Gianella, Hunt). Merck will provide study drug for this trial to assess mucosal CMV shedding and biomarkers of systemic inflammation at multiple timepoints. 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 treating CMV with letermovir 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.

抽象的如果我们忽视维持艾滋病毒的炎症机制，艾滋病毒治疗努力可能会继续徒劳。艾滋病毒的持续存在。科学前提：HIV 感染者 (PWH) 炎症的常见驱动因素是巨细胞病毒 (CMV)，几乎普遍共同感染感染者。在这种双重感染期间，亚临床 CMV 复制频繁且深刻影响免疫系统，包括几种 CMV 驱动的促进 HIV 的机制即使在抗逆转录病毒治疗（ART）期间也是如此。其中一些机制可能会扭曲 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 细胞包含 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 持续存在至关重要艾滋病治疗工作。拟议研究的优势在于它将使用最先进的方法并利用先前的 NIH- 作为 ACTG 资助的随机安慰剂的一部分，投资收集适当的生物样本和数据抗巨细胞病毒药物莱特莫韦的对照试验（A5383，联合主席：Gianella，Hunt）。默克公司将提供研究药物该试验旨在评估多个时间点的粘膜巨细胞病毒脱落和全身炎症的生物标志物。研究设计：我们的项目旨在仔细、严格地阐明 CMV 驱动机制，影响艾滋病毒的持续存在。目标 1 将确定如何直接检测各种病毒抗原（CMV、流感、EBV 和 HIV）诱导 HIV 感染的 CD4+ T 细胞离体克隆扩增。目标 2 将评估治疗的间接效果 CMV 与莱特莫韦对 HIV 储存库和体内 T 细胞库的影响。阐明离体的机制途径以及目标 1 和 2 中的体内观察，我们将描述与相关的特定免疫机制克隆扩张和炎症与 CMV 和 HIV 持续存在相关。总体目标：如果我们忽视维持艾滋病毒的炎症机制，艾滋病毒治疗努力可能会徒劳无功。艾滋病毒储存库。该项目符合 NIH OAR 优先事项，因为它将评估病毒传播的机制抗原（CMV、EBV、流感和 HIV）通过携带 CD4+ T 细胞的扩增来影响 HIV 的持续存在 HIV DNA（目标 1）。此外，我们将确定抑制 CMV 对减少免疫功能障碍的益处和 HIV 细胞储存库（目标 2 和 3）。影响：拟议项目将通过确定如何用莱特莫韦抑制 CMV 产生有意义的影响可能会影响炎症、免疫功能障碍和艾滋病毒储存库。生成的结果将推进艾滋病毒治疗和感染者卫生保健议程。