Neuroimmune and Cognitive Consequences of Nicotine Use in a Rodent Model of HIV: Implications for Anti-Retroviral Therapies

PROJECT SUMMARY/ABSTRACT This A-START R03 will examine the role of volitional nicotine use in exacerbating neuroimmune consequences of HIV using a rat model in support of a larger R01. Clinically, persons living with HIV (PLWH) are 2-3 times more likely than the average population to use nicotine-containing products and are less likely to quit. Further, combined anti-retroviral therapy (cART) does not reverse neurocognitive impairments induced by HIV infection, and PLWH often present with comorbid anxiety and depression, which smoking is used as a coping strategy. Despite these clinical associations, the mechanisms underlying these relationships have not been thoroughly examined using preclinical models, which can provide sensitive assessments of these relationships. We have found that chronic nicotine self-administration (SA) is associated with neurobiological adaptations within the neuroimmune system of the nucleus accumbens core (NAcore) region of the addiction/reward pathway. The prefrontal cortex (PFC) and amygdala, additional regions within the reward pathway, has been shown to play a role in preclinical models of drug use, cognition, and anxiety and thus may play a role in nicotine/HIV interactions. Our preliminary data show that NAcore cytokine profiles are suppressed by nicotine SA, and microglia are sex- specifically impacted by nicotine use whereby females show heightened vulnerability. Conversely, we show that blood serum pro-inflammatory cytokines are increased following nicotine SA in females. We further show that nicotine seeking is critically regulated by NAcore microglia, indicating that these neuroimmune cells may have outsized control over nicotine-motivated behavior. Together, these immune consequences of nicotine use may have implications for PWH because HIV is characterized by profound inflammation. We hypothesize that chronic volitional nicotine SA improves HIV-associated neurocognitive disorders (HAND) and anxiety, but exacerbates HIV-induced neuroimmune signaling, leading to greater use motivation. Here we will utilize the EcoHIV viral construct during nicotine SA to recapitulate microglial infection, as well as neurocognitive impairments and anxiety-like behavior seen in the clinical condition. We will evaluate if chronic nicotine SA enhances cognitive functioning as measured via delayed matching to sample (DMTS), a memory task, and anxiety-like behaviors in open field testing (Aim 1), and if this is associated with enhanced NAcore, PFC, and amygdala microglial reactivity both in EcoHIV-infected and non-infected microglia (Aim 2). We will further test if nicotine and EcoHIV interact to further dysregulate NAcore, PFC, amygdala, and blood serum cytokine profiles (Aim 2). Importantly, we will test the ability of cART treatment to impact these neurobehavioral endpoints. These studies will define how nicotine-induced changes in neuroimmune signaling are impacted by EcoHIV infection, a better understanding of how nicotine’s volitional exposure may influence cognitive performance and anxiety- like behavior, and how ART may impact these effects which will lead to a larger R01 to fully examine sex-specific novel neurobiological mechanisms of immune system dyshomeostasis after EcoHIV infection and nicotine use.