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.

HIV reservoirs and meth use grant. M. Stevenson, H. Tookes, PIs. A. Carrico, L Ndhlovu Co-Is Project Narrative This project will assess whether use of meth by HIV-1 infected MSM triggers activation of viral reservoirs and whether this correlates with an increase in HIV clinical disease markers. The project will use novel molecular approaches to assess HIV reservoirs within infected MSM who use meth. This information will provide a fuller understanding of how drug use promotes clinical disease progression in the face of antiviral therapy.