Nicotine and neurocognition in HIV: Translational challenges and therapeutic potential.

Approximately half of people with HIV (PWH) experience neurocognitive impairment (NCI), despite antiretroviral therapies that have turned what was formerly a death sentence to a chronic illness. No targeted treatments exist for HIV-associated NCI, impacting long-term quality of life. Smoking rates in PWH are nearly double those of the general population, and with evidence for pro-cognitive effects of nicotine, this may reflect self-medication. However, clinical studies yield inconsistent findings-some showing benefits, others reporting harm-likely due to variability in nicotine exposure methods, cognitive testing paradigms, withdrawal states, and confounding comorbidities. In contrast, animal studies offer a more controlled framework to isolate the effects of nicotine. Preclinical models suggest that nicotine may mitigate HIV-associated cognitive deficits by acting on α7 nicotinic acetylcholine receptors (nAChRs), leading to reduced neuroinflammation. These findings highlight the therapeutic potential of targeting nAChRs, though mechanisms remain incompletely understood. Despite the clarifications offered by preclinical work, translation to human models remains challenging, with key challenges including variability in defining nicotine use, route of administration, confirming mechanism of action, and controlling for comorbidities. Future studies could utilize vaping mechanisms, self-administration paradigms, and translational cognitive assessments to clarify the potential for nicotine and nAChR agonists to attenuate NCI. While nicotine-based therapies show promise, their risks-particularly smoking-related health complications in PWH-must be considered, hence the need to discover potential pro-cognitive mechanisms of action.