Mechanisms of CMV Replication on HIV Persistence

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，艾滋病毒治疗努力很可能继续徒劳。 科学前提：艾滋病毒携带者(PWH)炎症的常见驱动因素是巨细胞病毒(CMV)，它几乎普遍合并感染PWH。在这种合并感染期间，亚临床CMV复制频繁并深刻影响免疫系统，包括几种促进HIV持续存在的CMV驱动机制，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使HIV前病毒优先整合到CMV特异性的CD4+T细胞中。此外，由于CMV特异性的CD4+T细胞占所有CD4+T细胞的很大比例，因此了解它们如何有助于HIV的持久性对于HIV的治疗工作至关重要。 拟议研究的优势在于，它将使用最先进的方法，并将利用NIH之前的投资来收集适当的生物检验剂和数据，作为ACTG资助的抗CMV药物letermovr(A5383，联席主席：Gianella，Hunt)以及抗CMV疫苗三联体(A5355，主席：Sara Gianella)的随机试验的一部分。 研究设计：我们的项目旨在仔细而严格地阐明影响HIV持久性的CMV驱动机制。目的1确定不同病毒抗原(CMV、流感病毒、EBV和HIV)如何在体外直接诱导HIV感染的CD4+T细胞的克隆性增殖。目的2评价利特莫韦或疫苗抑制巨细胞病毒对体内HIV蓄积库和T细胞库的间接影响。为了阐明AIMS 1和AIMS 2中体外和体内观察的机制，我们将表征与CMV和HIV持久性相关的克隆性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宿主的炎症机制，艾滋病毒治疗努力很可能是徒劳的。该项目与NIH OAR的优先事项一致，因为它将评估病毒抗原(CMV、EBV、流感和艾滋病毒)通过扩增携带艾滋病毒DNA的CD4+T细胞影响艾滋病毒持久性的机制(目标1)。此外，我们将确定抑制CMV以减少免疫功能障碍和艾滋病毒细胞库的好处(目标2和3)。 影响：拟议的项目将通过确定用来特莫韦抑制CMV可能如何影响炎症、免疫功能障碍和艾滋病毒宿主而产生有意义的影响。所产生的结果将推进艾滋病毒治疗和威斯康星医院健康议程。

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.