Mechanisms of CMV Replication on HIV Persistence

摘要 如果我们忽视维持艾滋病毒感染的炎症机制，那么艾滋病毒治疗的努力可能会继续是徒劳的。 艾滋病毒的持续存在。 科学假设：HIV感染者（PWH）炎症的一个常见驱动因素是巨细胞病毒（CMV）， 这种病毒几乎普遍会同时感染威尔斯亲王医院在这种合并感染期间，亚临床CMV复制频繁， 深刻影响免疫系统，包括几个CMV驱动的机制，促进艾滋病毒 即使在抗逆转录病毒治疗（ART）期间也存在持续性。其中一些机制可能会扭曲艾滋病毒前病毒 倾向于优先整合到CMV特异性CD 4 + T细胞中。此外，由于CMV特异性CD 4 + T细胞包含 在所有CD 4 + T细胞中占很大比例，因此了解它们如何导致HIV持续存在至关重要 艾滋病治疗工作。 拟议研究的优势在于，它将使用最先进的方法，并将利用先前的NIH- 投资收集适当的生物标本和数据，作为ACTG资助的随机安慰剂的一部分， 抗CMV药物莱特莫韦的对照试验（A5383，联合主席：Gianella，Hunt）。默克将提供研究药物 本试验旨在评估多个时间点的粘膜CMV脱落和全身性炎症的生物标志物。 研究设计：我们的项目旨在仔细和严格地阐明CMV驱动的机制， 影响艾滋病毒持久性。目的1将确定各种病毒抗原（CMV，流感病毒，EBV和HIV）如何直接 体外诱导HIV感染CD 4 + T细胞克隆扩增。目标2将评估治疗的间接效果 CMV与莱特莫韦对体内HIV储库和T细胞库的影响为了阐明离体的机制途径， 以及目标1和2中的体内观察，我们将描述与以下相关的特定免疫机制： 与CMV和HIV持续存在相关的克隆扩增和炎症。 总体目标：如果我们忽视维持艾滋病毒感染的炎症机制， 艾滋病病毒库。该项目符合NIH OAR的优先事项，因为它将评估病毒感染的机制。 抗原（CMV，EBV，流感病毒和HIV）通过携带HIV的CD 4 + T细胞的扩增影响HIV的持久性。 HIV DNA（Aim 1）。此外，我们将确定抑制CMV以减少免疫功能障碍的益处 和HIV细胞库（目标2和3）。 影响：拟议的项目将通过确定如何用莱特莫韦抑制CMV产生有意义的影响 可能影响炎症、免疫功能障碍和HIV储存库。产生的结果将推动 艾滋病毒治疗和威尔斯亲王医院的健康议程。

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.