Project Summary/Abstract Persons with HIV (PWH) remain at an 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 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-24-003, which calls for applications that “identify and characterize common and specific inflammasome pathways” activated by illicit drugs and HIV, quantify “the impact of inflammasome activation on cognition and behavior,” evaluate “inflammasome signatures … and their use as biomarkers of neuroinflammation in PWH and substance use disorders (SUD),” and determine the “structural and functional consequences of inflammasome activation in different anatomical brain regions under the influence of SUD and HIV.” The proposed project responds to this call with a large-scale, innovative, dynamic functional mapping and molecular markers study that leverages multiple recent discoveries to identify the role(s) of inflammasome activation in the mechanisms and overall pathways underlying HIV-related inflammation and cognitive decline, as well as the impact of regular cannabis use on these parameters in virally suppressed PWH. Specifically, Aim 1 examines whether the neural oscillations and circuitry serving working memory and attention are modulated by inflammasome activity and/or the mitochondrial redox environment, which builds on our work featured in PNAS and Brain, Behavior, and Immunity that the superoxide-sensitive mitochondrial redox environment differentially predicts cognitive performance and the underlying neural oscillations in controls and PWH. Aim 2 quantifies the impact of regular cannabis use on inflammasome activity and the mitochondrial redox environment and follows on the heels of our finding that mitochondrial function differentially modulates superoxide in PWH relative to controls, and that superoxide predicts neuroinflammatory levels and cognitive function. Finally, Aim 3 builds on our recent finding that cannabis suppresses the pathological spontaneous cortical activity that is observed in PWH, and is accentuated in cognitively impaired PWH, by identifying whether these cannabis-induced effects are mainly driven by normalization of the mitochondrial redox environment, inflammasome activation, or both. These recent, major scientific advances provide an ideal foundation to directly address the key objectives of this RFA through an innovative project that uses state-of-the-art neuroimaging and systems biology methods to build on an established model of neuroinflammation that has been linked to cognitive and neural dysfunction in PWH.

Project Narrative Persons infected with HIV now have a life expectancy near that of the general population, but they remain at a significantly higher risk of developing cognitive impairment. Recent human neuroimaging studies have identified the cortical brain circuits that are centrally involved in such cognitive decline, but the underlying pathways and molecular mechanisms remain poorly understood, and the potential therapeutic options are very limited. The current project builds on several recent discoveries and will use advanced dynamic functional brain mapping, systems biology approaches, and high-dimensional structural equation modeling to identify whether parameters of inflammasome activation and/or the mitochondrial redox environment drive cognitive and brain dysfunction in persons with HIV, and whether regular cannabis use therapeutically modulates these parameters.