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

摘要： 这项提案的目的是提供机制的见解如何甲基使用改变单核细胞表观遗传 景观和病毒库动态影响治疗的HIV感染的临床进展。 甲基苯丙胺（METH）使用的强劲复苏正在助长三分之一的新艾滋病毒感染 在MSM中[1]。虽然大多数使用METH的MSM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，至少一种病毒载量> 200拷贝/mL）超过15个月[2]。也有证据表明 即使在调整HIV疾病后，METH和其他兴奋剂的使用也可预测更快的临床HIV进展 [3]，[4]，[5]。人们对生物行为机制知之甚少， 甲基苯丙胺的使用加速了艾滋病毒的发病。 我们已经证明，单核细胞炎症过程的宿主替代物是病毒感染的关键驱动因素， 免疫致病性和神经致病性（包括可溶性CD 14和CD 163 [sCD 14，sCD 163]）， 最近使用甲基苯丙胺加剧，并在注射甲基苯丙胺治疗艾滋病毒感染的MSM中扩大[5]，[6]， [7]，[9]。我们最近通过使用METH的HIV队列获得的初步数据进一步强调了这一点 表明使用METH的HIV受试者中单核细胞活化标志物（IL-6，sCD 14）相对于HIV受试者增加 只有科目。我们假设METH的使用破坏了单核细胞表观遗传景观， 免疫激活以及淋巴和骨髓细胞库动力学的持久变化， 治疗的HIV感染中的HIV发病机制。 我们建议评估METH的使用对生物活性储层动态的影响以及对 单核细胞的表观遗传景观。我们将访问METH的定义明确的队列资源（IDEA，CRUSH）- 使用MSM询问单核细胞表观遗传景观和病毒学替代物的病毒库 这是专门为揭示在高度脆弱的淋巴和骨髓水库的变化， 纵向抽样可能具有挑战性的主题。具体而言，我们建议： 目的1：评估单核细胞表观遗传景观和淋巴病毒库动力学， 使用或不使用METH的MSM中临床HIV进展和神经精神健康的替代物 有效的抗逆转录病毒治疗， 目的2：探讨抗逆转录病毒治疗有效的男男性接触者血浆病毒组， 自然中断ART以测量METH使用对体内骨髓储库激活的影响。 推进我们对METH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库动力学将指导方法的发展，以改善 METH使用对HIV感染治疗后临床进展影响

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.