ABSTRACT HIV-Associated Neurocognitive Disorders (HAND) is a significant comorbid condition for people living with HIV/ AIDS (PLWH). HAND is associated with HIV-induced neurotoxicity that dysregulates, injures, and in severe cases, causes death of neurons in the key brain regions that regulate neurocognition. Combined antiretroviral therapy (cART) inhibits active HIV-1 replication; but it has not reduced the prevalence of HAND, as it occurs in 30~50% of PLWH and is expected to increase as PLWH age. Notably, Cocaine (Coc) Use Disorders (CUD) are comorbid with HAND in many cases and worsen it severely. Ironically, although cART is absolutely necessary for treating HIV/AIDS, emerging data point to cART as a potential contributor to HAND through cART-induced neurotoxicity. This raises key questions regarding if chronic cART contributes to neurological/neurocognitive deficits linked to HAND; and how it alters brain neuron activity in the context of neuroHIV and CUD; both are the focus of this proposal. Our studies suggest that cART induces neuronal Ca2+ dysregulation in the medial prefrontal cortex (mPFC, a key regulator of neurocognition and addiction), similar to that well-described in neuroHIV and CUD mediated by overactive voltage-gated L-type Ca2+ channels (L-channels) and NMDA receptors (NMDARs). Dysfunction of mPFC pyramidal neurons is linked to HAND, CUD and many other neuro- degenerative diseases. Thus, we hypothesize that cART-induced mPFC neuronal Ca2+ dysregulation worsens similar dysfunction caused by neuroHIV and Coc; and that is reduced by combined antagonism of L -channel/ NMDAR overactivation. We will determine the effects of cART, neuroHIV and Coc on mPFC pyramidal neurons, and elucidate their underlying mechanism. Specifically, we will use three combined rat models of (i) cART (chronic Triumeq, a 1st-line cART regimen consisting of 3 antiretroviral drugs - abacavir, dolutegravir and lamivudine), (ii) neuroHIV (HIV-1 transgenic rats), and (iii) Coc abuse (Coc self-administration, Coc-SA), to elucidate the long-term effects of cART in vivo on mPFC neuronal activity and their mechanism in the context of neuroHIV and CUD (Aim1); define the effects of chronic cART on interactive astrocyte/neuron dysfunction in the mPFC under neuroHIV and CUD conditions (Aim2); and identify the effects of combined antagonism of excessive Ca2+ influx/ [Ca2+]in that alleviate neuronal activity and cognitive behavior in the context of neuroHIV/ CUD (Aim3). Further, we will also define HIV/cART/Coc-induced neuron/astrocyte dysfunction in post-mortem HIV+ human brains (Exploratory Aim) to provide additional support for the principal concept and hypothesis of this proposal. Together, the proposed research will elucidate the mechanism by which neuroHIV, chronic cART in vivo and Coc-SA, individually and jointly, alter mPFC neuronal activity, and in such process identify the key mechanistic targets that will inform therapeutic intervention for HAND and CUD in the era of cART.

PROJECT NARRATIVE People living with HIV (PLWH) are living longer due to the success of anti-HIV therapy to suppress HIV, yet they still experience neurocognitive impairments that are worsened in many cases by chronic cocaine abuse, and vice versa. The mechanism for such HIV/cocaine-induced brain dysfunction is not entirely clear; but a component that should be carefully looked at is the aberrant effects of the anti-HIV therapeutic medicines themselves on the brain, which are similar to those induced by HIV and cocaine. In this study, we will determine the effects of such anti-HIV medicines on the brain neurons in the context of HIV/AIDS and cocaine abuse (both cause neurocognitive impairments), and will do so in small animal models of them; and that can potentially shed some lights on the role of anti-HIV drugs in the brain, elucidate how HIV, anti-HIV drugs and cocaine alter the brain function, and provide a novel therapeutic approach for treating HIV/AIDS and cocaine addiction.