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.

抽象的如果我们忽略维持炎症机制，艾滋病毒治愈的努力可能会继续徒劳艾滋病毒的持久性。科学前提：艾滋病毒（PWH）患者的炎症驱动力是巨细胞病毒（CMV），几乎普遍共同感染了PWH。在此共同感染期间，亚临床CMV复制频繁，并且深刻影响免疫系统，包括促进HIV的几种CMV驱动的机制即使在抗逆转录病毒疗法（ART）期间，持久性也是如此。这些机制中的一些可能偏向HIV病毒朝向优先集成到CMV特异性CD4+ T细胞中。另外，作为CMV特异性CD4+ T细胞所包含所有CD4+ T细胞中很大一部分，因此了解它们如何对HIV持久性贡献将是必不可少的为了治愈艾滋病毒。拟议的研究的优势是，它将使用最新方法，并利用先前的NIH- 作为ACTG资助的随机安慰剂的一部分，以收集适当的生物测量和数据的投资抗CMV药物Letermovir的对照试验（A5383，联合主席：Gianella，Hunt）。默克将提供学习药物为了评估在多个时间点上全身炎症的粘膜CMV脱落和生物标志物。研究设计：我们的项目旨在仔细，严格地阐明CMV驱动的机制影响艾滋病毒的持久性。 AIM 1将直接确定各种病毒抗原（CMV，流感，EBV和HIV）如何在体内诱导HIV感染的CD4+ T细胞的克隆扩张。 AIM 2将评估治疗的间接效果在艾滋病毒储层上与letermovir的CMV和体内的T细胞库。澄清离体的机械途径在AIM 1和2中的体内观察结果，我们将表征与之相关的特定免疫机制克隆扩张和炎症与CMV和HIV持久性相关。总体目标：如果我们忽略维持的炎症机制，艾滋病毒治愈的努力可能是徒劳的艾滋病毒水库。该项目符合NIH OAR优先级，因为它将评估病毒的机制抗原（CMV，EBV，流感和HIV）通过携带CD4+ T细胞的扩展影响HIV的持久性 HIV DNA（目标1）。此外，我们将确定抑制CMV减少免疫功能障碍的好处和艾滋病毒细胞库（目标2和3）。影响：拟议的项目将通过确定如何抑制Letermovir的CMV产生有意义的影响可能会影响炎症，免疫功能障碍和HIV库。生成的结果将促进 HIV治疗和PWH健康议程。