Molecular mechanisms: Dysregulation of monoamine transporters by HIV-1Tat and cocaine

People living with HIV (PLWH) face a high risk of neurocognitive impairments in depression and experience higher levels of impulsivity. The lifetime prevalence of cognitive depression in PLWH is twice that of HIV seronegative individuals. Cocaine abuse has been shown to enhance the incidence of HIV-1 associated cognitive depression and exacerbate its severity. Prolonged exposure to HIV-1 viral proteins causes dysregulation of monoamine transmission despite the advent of combination antiretroviral therapies (cART), which has been implicated as a key factor in developing impulsivity, cognitive depression, and cocaine abuse among HIV positive population. Results from our previous funding cycles have demonstrated that in vivo expression of HIV-1 Tat protein dysregulates monoamine transmission by its allosteric interaction with dopamine (DA) transporter (DAT) and norepinephrine transporter (NET) in inducible Tat transgenic (iTat-tg) mice. Furthermore, our preliminary in vitro and in vivo studies demonstrate that the in vivo Tat expression increases serotonin (5-HT) release and decreases 5-HT uptake through serotonin transporter (SERT) in the midbrain of iTat-tg mice, however, EcoHIV infection decreases 5-HT release in the midbrain and SERT- mediated 5-HT uptake in hippocampus of humanized mice for chronic HIV infection. These findings suggest that HIV-1 viral proteins dysregulate monoamine homeostasis via inhibition of monoamine transporters, which may potentially increase vulnerability to developing impulsivity, cognitive depression, and cocaine abuse in HIV-infected individuals. Studying single Tat protein allow us to identify targets in the brain for Tat binding and develop therapeutic intervention for HIV-induced neurological damages. Indeed, a novel allosteric inhibitor of monoamine transporters, SRI-32743, attenuates not only Tat-inhibited DA transport via DAT but also 5-HT uptake via SERT, and alleviates Tat-potentiated cognitive impairments and depressive-like behaviors. We hypothesize that HIV-1 Tat, acting via the unique binding sites, perturbs the monoamine transporter regulatory network and exacerbates cocaine-induced pathophysiological changes in monoaminergic transmission, resulting in impulsivity and depressive-like behaviors in the context of NeuroHIV. Three specific aims are proposed in investigating this hypothesis: (1) through computational modeling and experimental validation, identify the recognition binding pockets on human SERT for Tat, cocaine, allosteric modulator and explore the potential interactions with Tat and cocaine, (2) characterize the pathophysiological role of the SERT in Tat- and cocaine-dysregulated monoaminergic transmission, and (3) perform the proof-of-concept studies using a pharmacological approach with chemical probes to establish their potential for therapeutic application in treating impulsivity and depression. Collectively, this proposal is anticipated to provide both new therapeutics and mechanistic insights into how HIV promotes dysregulation of monoamine transmission in the context of poor impulsivity control, cognitive depression, and cocaine abuse.