Mechanisms of CMV Replication on HIV Persistence

CMV 复制对 HIV 持续存在的机制

• 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
• 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

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.

摘要