Project Summary/Abstract Persons with HIV (PWH) in the western world have a life expectancy near that of the general population, yet they remain at a significantly elevated risk of developing cognitive impairments. Such impairments are the most common neurological complication of HIV disease, and research targeting these comorbidities is one of four overarching priorities identified by the Office of AIDS Research (NOT-OD-20-018). Recent human neuroimaging studies have broadly shown that the milder impairments more frequently observed in virally-suppressed PWH arise from multiple cortical circuits, which is a major paradigm shift from the putative subcortical origins of the severe cognitive impairments observed earlier in the epidemic. However, despite this progress, we still have a limited understanding of the molecular precursors and pathways that lead to dysfunction in these cortical circuits, and virtually no viable therapeutic options, with only limited potential avenues (e.g., cannabis) on the horizon. This proposal responds to RFA-DA-22-012, which calls for applications that “define HIV-associated persistent inflammation and its causal link to HIV-related comorbidities such as … neurological disorders,” “explore the interaction between HIV immune activation and cannabinoid use as it pertains to neurological disorders,” and “characterize and validate the potential anti-inflammatory, immune stabilizing (beneficial) properties of canna- binoids in chronic HIV infection.” The proposed project responds to this call with an innovative, large-scale, dynamic neuroimaging and molecular markers study that leverages multiple recent discoveries to identify the impact of cannabis use on the mechanisms and pathways underlying HIV-related persistent inflammation and decline in cognitive and brain function in virally-suppressed PWH. Each of our aims builds on a major discovery in 2021. Specifically, Aim 1 examines whether cannabis use modulates the superoxide-sensitive mitochondrial redox environment and neuroinflammation in PWH, which follows on the heels of our finding that mitochondrial function differentially modulates superoxide in PWH compared to controls, and that the latter predicts neuro- inflammation and cognitive function. Aim 2 identifies whether attention- and motor-related neural oscillations are directly modulated by the same superoxide-sensitive pathway in PWH, which builds on our major discovery featured in PNAS that the superoxide-sensitive mitochondrial redox environment predicts cognitive performance and the underlying neural oscillations in controls. Finally, Aim 3 builds on our recent breakthrough that cannabis suppresses the pathological spontaneous cortical activity that is observed in PWH, and further accentuated in cognitively impaired PWH, by examining whether these cannabis-induced alterations are mediated by the superoxide-sensitive mitochondrial redox environment. These recent, major scientific advances provide an ideal foundation to directly address the key objectives of this RFA through an innovative project that utilizes state-of- the-art neuroimaging and systems biology methods, and builds on an established model of neuroinflammation in PWH that has been linked to cognitive and neural function in healthy adults and cognitive decline in PWH.

Project Narrative Persons infected with HIV now have a life expectancy that approaches that of the general population, but they remain at a significantly elevated risk of developing cognitive impairments. Recent neuroimaging studies have identified the cortical brain circuits that are centrally involved in these generally mild cognitive impairments, but the underlying molecular mechanisms remain poorly understood, and the potential therapeutic options are very limited. The current project builds on several important discoveries in 2021 and will use advanced dynamic functional brain mapping, systems biology approaches, and structural equation modeling to determine whether parameters of the mitochondrial redox environment drive neuro-inflammation in persons with HIV and whether chronic cannabis use modulates these parameters, with the long-term goal of identifying viable therapeutics.