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

甲基苯丙胺使用、病毒库动态与治疗艾滋病毒感染的临床进展之间的关系

• 批准号: 10683495
• 负责人: Adam Wayne Carrico
• 金额: $ 66.4万
• 依托单位: UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-06-01 至 2028-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10683495
• 关键词: Acceleration; Address; Antiviral Therapy; Binding; Biological Assay; CD14 gene; CD4 Positive T Lymphocytes; Cells; Cellular Assay; Clinical; Collaborations; Cross-Sectional Studies; DNA; DNA Methylation; Data; Development; Disease Marker; Disease Progression; Drug usage; Enrollment; Epigenetic Process; Evaluation; Genetic Transcription; Goals; Grant; HIV; HIV Infections; HIV-1; Harm Reduction; Health; Immune System Diseases; Immunologic Markers; In Vitro; Individual; Inflammation; Inflammation Process; Interleukin-6; Interruption; Lymphoid; Lymphoid Cell; Macrophage; Methamphetamine; Modernization; Molecular; Myelogenous; Myeloid Cell Activation; Myeloid Cells; Neuroimmune; Neuropathogenesis; Pathogenesis; Patient Self-Report; Pharmaceutical Preparations; Plasma; Protocols documentation; Research Personnel; Resources; Risk; Sampling; Services; Surrogate Markers; TNF gene; Viral; Viral Load result; Viral Markers; Viral reservoir; Virus Activation; Vulnerable Populations; antiretroviral therapy; biobehavior; clinical phenotype; cohort; experience; follow-up; immune activation; in vivo; insight; men who have sex with men; methamphetamine use; methylation pattern; microbial; minimally invasive; monocyte; neuropsychiatry; novel; peer; prospective; reactivation from latency; stimulant use; substance use; therapy adherence; viral DNA; viral RNA; viral rebound; virome

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.

抽象的： 该提案的目的是提供机械洞察力，了解如何使用甲基甲基的使用改变单素质的表观遗传学 景观和病毒储层动力学影响治疗的HIV感染的临床进展。 甲基苯丙胺（甲基苯丙胺（Meth））的使用很强 在MSM [1]中。尽管大多数使用MET的MSM可以在现代反抗事中获得病毒抑制 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 在15个月内，病毒学反弹（即至少一个病毒载荷> 200份/ml）[2]。也有证据表明 甲基苯甲酸和其他刺激剂的使用预测临床HIV进展，即使调整了HIV疾病 标记和自我报告的艺术依从性[3]，[4]。关于生物行为机制知之甚少 甲基使用加速HIV发病机理。 我们已经证明，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 免疫发育性和神经病发育性（包括可溶性CD14和CD163 [SCD14，SCD163]），是 最近使用甲基甲基苯丙胺的使用并在MSM中扩增的MSM会加剧，他们在治疗的HIV感染中注入甲基苯丙胺[5]，[6]， [7]，[9]。这进一步强调了我们最近使用HIV队列获得的甲基苯丙胺获得的最新初步数据 表明使用HIV相对于HIV，单核细胞激活标记（IL-6，SCD14）的增加 只有主题。我们假设甲基甲基的使用会破坏单核细胞表观遗传景观，以赋予长期 免疫激活以及淋巴样和髓样细胞储存动力学的持久变化 治疗的HIV感染中的HIV发病机理。 我们建议评估甲基甲基的使用对生物学胜任储层的动态以及对 单核细胞的表观遗传景观。我们将访问甲基苯丙胺的定义明确的队列资源（想法，粉碎） 使用MSM询问单核细胞表观遗传景观和病毒式替代的病毒储层 该量身定制的是揭示高度脆弱的淋巴机和髓样储层的储层变化 纵向抽样的受试者可能会具有挑战性。具体来说，我们建议： 目标1：评估单核细胞表观遗传景观和淋巴病毒储层动力学和 MSM中临床HIV进展和神经精神健康的替代物，他们使用或不使用MET 关于有效的艺术和自然中断艺术的人， 目标2：询问MSM中的等离子体病毒蛋白有关有效的艺术，他们使用或不使用甲基苯丙胺以及谁 自然中断艺术，以衡量甲基苯丙胺对体内髓样储层激活的影响。 促进我们对甲基甲基的基本机制改变单核细胞的基本理解 表观遗传景观和病毒储层动力学将指导改善方法的发展 甲基苯丙胺对治疗的HIV感染中临床进展的影响。