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.

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