Mechanisms of CMV Replication on HIV Persistence

摘要 如果我们忽视维持艾滋病的炎症机制，艾滋病毒的治疗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)患者炎症的一个常见驱动因素是巨细胞病毒(CMV)， 几乎普遍合并感染威斯康星病毒。在这种混合感染过程中，亚临床CMV复制频繁， 深刻影响免疫系统，包括几种由CMV驱动的促进艾滋病毒的机制 坚持，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艾滋病毒前病毒 更倾向于优先整合到CMV特异性的CD4+T细胞。此外，由于CMV特异性的CD4+T细胞包括 占所有CD4+T细胞的很大比例，因此了解它们如何有助于艾滋病毒的持久性将是至关重要的 用于治疗艾滋病毒的努力。 拟议研究的优势在于，它将使用最先进的方法，并将利用之前的NIH- 投资收集适当的生物制剂和数据，作为ACTG资助的随机安慰剂的一部分- 抗CMV药物Letermovir的对照试验(A5383，联合主席：Gianella，Hunt)。默克公司将提供研究药物 这项试验评估了多个时间点的粘膜CMV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而严格地阐明CMV驱动的机制 影响艾滋病毒的持久性。目标1将直接确定各种病毒抗原(CMV、流感、EBV和HIV)如何 体外诱导HIV感染的CD4+T细胞的克隆性增殖。目标2将评估治疗的间接效果 CMV与莱特莫韦在体内对HIV储备库和T细胞谱系的影响。阐明体外实验的机制途径 在AIMS 1和AIMS 2的活体观察中，我们将表征与以下相关的特定免疫机制 与CMV和HIV持续相关的克隆性扩张和炎症。 总体目标：如果我们忽视维持艾滋病毒感染的炎症机制，艾滋病毒的治疗努力可能是徒劳的 艾滋病毒蓄水池。该项目符合NIH OAR的优先事项，因为它将评估病毒 抗原(CMV、EBV、流感和HIV)通过扩增携带HIV的CD4+T细胞来影响HIV的持久性 艾滋病毒DNA(目标1)。此外，我们将确定抑制巨细胞病毒以减少免疫功能障碍的益处。 和艾滋病毒细胞储存库(目标2和3)。 影响：拟议的项目将通过确定如何用letermovir抑制CMV来产生有意义的影响 可能会影响炎症、免疫功能障碍和艾滋病毒宿主。生成的结果将使 艾滋病毒治疗和威斯康星医院健康议程。

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.