People with HIV (PWH) who use stimulants experience profound intersectional stigma and discrimination that can cause considerable psychosocial stress. An overactive, unresolved stress response fuels systemic inflammation, which may be a common pathway linking psychosocial stressors to complex neuropathology in HIV. Chronic stress can disrupt central nervous system functions that regulate reward processing. Our team and others have shown that these pathophysiologic alterations are amplified by stimulant use and potentiate neuropsychiatric symptoms. However, the inflammatory mechanisms through which stress affects brain networks that subserve substance use and psychiatric multi-morbidity in HIV remain unknown. The overarching goal of this proposal is to identify neuroimmune mechanisms that underlie the intersection of social stigma, anhedonia, and altered reward processing in PWH who use stimulants (e.g., cocaine, methamphetamine). Embracing the experimental rigor of a randomized controlled trial (RCT) design, we will leverage an evidence-based positive affect intervention (ARTEMIS) as a mechanistic probe to elucidate the neural and immunologic substrates linking psychosocial stress to substance use and depression in PWH. With this translational approach, we aim to: (1) Investigate the causal link between ARTEMIS-induced improvements in anhedonia and neural functioning in reward circuitry using resting-state and task-based functional MRI; (2) Evaluate the effects of ARTEMIS on transcriptional control pathways and downstream markers of peripheral inflammation; and (3) Test whether reductions in proinflammatory markers have positive feedback on reward functioning and stimulant use. To achieve these specific aims, we will enroll 189 PWH who currently use stimulants and have suppressed HIV viral load. Participants will be randomly assigned on a 2:1 ratio to receive ARTEMIS or a wait-list control. To support durable HIV viral suppression throughout the trial, all participants will receive smartphone-based contingency management for ART adherence. Assessments at 3- and 6-month follow-ups will characterize changes in neural functioning and leukocyte signaling as plausible mediators of ARTEMIS effects on behavioral outcomes. Our innovative and clinically important proposal is highly responsive to RFA-DA-24-005 and will advance our basic understanding of the neuroimmune pathways underlying psychological resilience to social stress that may mitigate substance use and depression in PWH. This proposal provides a scientifically rigorous model for examining the causal associations amongst these prevalent comorbidities in a population that is critical to ending the HIV epidemic, while also providing participants with the benefit of an evidence-based intervention with a transdiagnostic target. The results of this mechanistic trial will identify preclinical targets for novel pharmacotherapies linked to reward circuitry.

Public Health Relevance Stimulant use disorder and depression are both more common in people with HIV (PWH) than in the general population and often co-occur, particularly in the context of chronic psychosocial stress. Psychosocial stress interacts with stimulant use and depression to compromise neuroimmune function and exacerbate central nervous system pathology associated with HIV disease, but the mechanisms that mediate these relationships are not well understood. Using a randomized controlled trial design, this study applies an evidence-based intervention that boosts positive affect in PWH to advance our understanding of the causal associations amongst these prevalent comorbidities in a population that is critical to ending the HIV epidemic.