Advancing the preclinical study of comorbid neuroHIV and substance use disorders: Current perspectives and future directions.

Human immunodeficiency virus (HIV) remains a persistent public health concern throughout the world. Substance use disorders (SUDs) are a common comorbidity that can worsen treatment outcomes for people living with HIV. The relationship between HIV infection and SUD outcomes is likely bidirectional, making clear interrogation of neurobehavioral outcomes challenging in clinical populations. Importantly, the mechanisms through which HIV and addictive drugs disrupt homeostatic immune and CNS function appear to be highly overlapping and synergistic within HIV-susceptible reward and motivation circuitry in the central nervous system. Decades of animal research have revealed invaluable insights into mechanisms underlying the pathophysiology SUDs and HIV, although translational studies examining comorbid SUDs and HIV are very limited due to the technical challenges of modeling HIV infection preclinically. In this review, we discuss preclinical animal models of HIV and highlight key pathophysiological characteristics of each model, with a particular emphasis on rodent models of HIV. We then review the implementation of these models in preclinical SUD research and identify key gaps in knowledge in the field. Finally, we discuss how cutting-edge behavioral neuroscience tools, which have revealed key insights into the neurobehavioral mechanisms of SUDs, can be applied to preclinical animal models of HIV to reveal potential, novel treatment avenues for comorbid HIV and SUDs. Here, we argue that future preclinical SUD research would benefit from incorporating comorbidities such as HIV into animal models and would facilitate the discovery of more refined, subpopulation-specific mechanisms and effective SUD prevention and treatment targets.