Relationship between methamphetamine use, viral reservoir dynamics and clinical progression in treated HIV infection

摘要： 这项提案的目标是提供有关冰毒使用如何改变单核细胞表观遗传学的机械性见解。 景观和病毒库动态影响艾滋病病毒感染治疗的临床进展。 甲基苯丙胺(冰毒)的使用强劲复苏，助长了三分之一的新艾滋病毒感染 在MSM[1]中。虽然大多数使用冰毒的男男性接触者可以在现代抗病毒治疗中实现病毒抑制 逆转录病毒疗法(ART)时代，我们团队和其他人的发现表明，大约一半的经验 病毒学反弹(即至少一个病毒载量200拷贝/毫升)超过15个月[2]。也有证据表明 冰毒和其他兴奋剂的使用预示着即使在对艾滋病毒疾病进行调整后，临床上艾滋病毒的进展也会更快 记号笔和自我报告的艺术坚持[3]，[4]。人们对生物行为机制知之甚少 冰毒的使用加速了艾滋病毒的发病。 我们已经证明了单核细胞炎症过程的宿主替代物，这是病毒的关键驱动因素 免疫致病性和神经致病性(包括可溶性CD14和CD163[sCD14，sCD163]) 由于最近使用冰毒而加剧，并在注射冰毒治疗艾滋病毒感染的男男性接触者中放大[5]，[6]， [7]、[9]。我们最近通过使用HIV队列的冰毒获得的初步数据进一步强调了这一点 表明使用冰毒的受试者单核细胞激活标志物(IL-6，sCD14)相对于HIV的增加 仅限受试者。我们假设冰毒的使用扰乱了单核细胞的表观遗传格局，从而传递了长时间的 免疫激活和淋巴和髓系细胞储存库动力学的持久变化 HIV感染治疗中的发病机制。 我们建议评估冰毒使用对具有生物能力的水库动态的影响，以及 单核细胞的表观遗传学图景。我们将访问定义明确的冰毒队列资源(想法，粉碎)- 用MSM询问单核细胞表观遗传格局和病毒学替代物的病毒库 它们是为揭示高度脆弱的淋巴和髓系储存库的变化而定制的 纵向抽样可能具有挑战性的对象。具体来说，我们建议： 目的1：评估单核细胞表观遗传格局和淋巴病毒储存库的动态和 使用或不使用冰毒的男男性行为者的临床HIV进展和神经精神健康状况的代用品 关于有效的艺术，以及谁自然地打断了艺术， 目的2：询问男男性接触者中谁使用或不使用冰毒的有效抗逆转录病毒疗法 自然中断抗逆转录病毒治疗，以评估冰毒使用对体内髓系储存库激活的影响。 促进我们对冰毒改变单核细胞的潜在机制的基本理解 表观遗传景观和病毒储藏库动力学将指导开发改善 冰毒的使用对HIV感染治疗的临床进展的影响。

Abstract: The goal of this proposal is to provide mechanistic insight into how METH use alters the monoocyte epigenetic landscape and viral reservoir dynamics to impact clinical progression in treated HIV infection. There is a strong resurgence of methamphetamine (METH) use that is fueling one-in-three new HIV infections in MSM [1]. Although the majority of MSM who use METH can achieve viral suppression in the modern anti- retroviral therapy (ART) era, findings from our team and others indicate that approximately half experience virologic rebound (i.e., at least one viral load > 200 copies/mL) over 15 months [2]. There is also evidence that METH and other stimulant use predict faster clinical HIV progression even after adjusting for HIV disease markers and self-reported ART adherence [3], [4]. Little is known about the bio-behavioral mechanisms whereby METH use accelerates HIV pathogenesis. We have demonstrated that host surrogates of monocyte inflammation processes, that are key drivers in viral immunopathogenicity and neuropathogenicity (including soluble CD14 and CD163 [sCD14, sCD163]), are exacerbated by recent METH use and amplified among MSM who inject METH in treated HIV infection [5], [6], [7], [9]. This is further underscored by our recent preliminary data obtained through a METH using HIV cohort indicating increases in monocyte activation markers (IL-6, sCD14) in METH using HIV subjects relative to HIV only subjects. We hypothesize that METH use disrupts the monocyte epigenetic landscape to impart long- lasting changes in immune activation and on lymphoid and myeloid cell reservoir dynamics that drives HIV pathogenesis in treated HIV infection. We propose to assess the impact of METH use on the dynamics of the biologically competent reservoir and on the epigenetic landscape of monocytes. We will access well-defined cohort resources (IDEA, CRUSH) of METH- using MSM to interrogate the monocyte epigenetic landscape and the viral reservoirs with virologic surrogates that are tailored to revealing reservoir changes in both lymphoid and myeloid reservoirs in highly vulnerable subjects where longitudinal sampling is likely to be challenging. Specifically, we propose to: Aim 1: Assess the monocyte epigenetic landscape and lymphoid viral reservoir dynamics and surrogates of clinical HIV progression and neuropsychiatric health in MSM who do or do not use METH on effective ART and who naturally interrupt ART, Aim 2: Interrogate the plasma virome in MSM on effective ART who do or do not use METH and who naturally interrupt ART to gauge the impact of METH use on myeloid reservoir activation in vivo. Advancing our basic understanding of the underlying mechanisms whereby METH alters the monocyte epigenetic landscape and viral reservoir dynamics will guide the development of approaches to ameliorate the impact of METH use on clinical progression in treated HIV infection.