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.

修改的项目摘要/摘要部分如果我们忽略维持艾滋病毒持续性的炎症机制，艾滋病毒治愈的努力可能会继续是徒劳的。科学前提：艾滋病毒（PWH）患者的炎症驱动力是巨细胞病毒（CMV），几乎普遍地共同感染了PWH。在此共同感染期间，亚临床CMV复制频繁，并深刻影响免疫系统，包括几种CMV驱动的机制，即使在抗逆转录病毒疗法（ART）期间，也可以促进HIV持久性。这些机制中的某些机制可能会使HIV病毒偏向优先整合到CMV特异性CD4+ T细胞中。同样，由于CMV特异性CD4+ T细胞占所有CD4+ T细胞的很大一部分，因此了解它们对HIV持久性的贡献对于HIV治疗的努力至关重要。拟议的研究的优势是，它将使用最先进的方法，并将利用先前的NIH投资来收集适当的生物测量和数据，这是ACTG资助的抗CMV药物Letermovir（A5383，联合队长：Gianella：Gianella，Hunt）的一部分，以及Anti-CMV vaccine and Anti-CMV vaccine faccine（A555555555555555555555555555555555553555555555555555555555）。研究设计：我们的项目旨在仔细，严格阐明影响HIV持久性的CMV驱动机制。 AIM 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细胞的克隆膨胀。 AIM 2将评估用Letermovir或疫苗抑制CMV对HIV储层和体内T细胞库的间接效应。为了澄清AIM 1和2中体内和体内观测的机械途径，我们将表征与克隆扩张和炎症相关的特定免疫机制，以及与CMV和HIV持久性相关的炎症。总体目标：如果我们忽略维持艾滋病毒水库的炎症机制，艾滋病毒治愈的努力可能是徒劳的。该项目符合NIH的优先级，因为它将评估病毒抗原（CMV，EBV，流感和HIV）的机制，通过扩展带有HIV DNA的CD4+ T细胞来影响HIV持久性（AIM 1）。此外，我们将确定抑制CMV减少免疫功能障碍和HIV细胞储存剂的好处（AIMS 2和3）。影响：拟议的项目将通过确定用Letermovir抑制CMV的影响可能会影响炎症，免疫功能障碍和HIV储量，从而产生有意义的影响。产生的结果将促进HIV治疗和PWH健康议程。