Hormonal and behavioral dysregulation following exposure to antiretrovirals and chronic cocaine

About This Grant

Project Summary Drug use increases HIV risk and worsens health outcomes in people living with HIV (PLWH). While antiretrovirals are effective for both prevention – using pre-exposure prophylaxis (PrEP) – and for treatment – using antiretroviral therapy (ART) – drug use further impairs medication adherence. It is thus essential to develop strategies to enable people who use drugs to achieve abstinence and prevent relapse, which is expected to reduce HIV risk, burden, and infection. Progesterone and its metabolites regulate drug craving and immune function, making them potential therapeutic targets. However, PLWH and people who use drugs often experience menstrual cycle disruptions, and the impact of PrEP or ART on hormone regulation remains unclear. Understanding these interactions could reveal strategies to reduce drug-seeking behavior and to improve HIV treatment outcomes. In our preclinical work using the EcoHIV mouse model of HIV infection, we observe disrupted estrous cyclicity, altered cytokine expression, and increased risk for cocaine relapse-related behavior. We further observe that ART restores estrous cyclicity and partially reverses altered brain cytokine expression in EcoHIV-infected mice. However, it is unknown whether ART restores cycle regularity in cocaine-exposed, EcoHIV-infected mice or whether PrEP interacts with drug exposure to affect hormonal function. The medial preoptic area (mPOA) regulates both estrous cyclicity and cocaine-related behavior, and our findings suggest EcoHIV infection increases mPOA activation in cocaine-exposed females. Progesterone and its active metabolite, allopregnanolone, act on both neurons and astrocytes. Thus, modulation of mPOA astrocytic and neuronal activity may represent a novel target for reducing drug seeking and neuroimmune dysregulation among those at risk of or living with HIV. This proposal will test the overarching hypothesis that chronic drug exposure and EcoHIV infection interact with antiretrovirals to promote estrous cycle irregularity and cocaine reinstatement via dysregulation of the mPOA. Aim 1 will assess how PrEP and ART impact estrous cyclicity, ovarian reserve, mPOA cellular activity, and neuroimmune signaling following chronic cocaine exposure. Aim 2 will use chemogenetic tools to determine the role of mPOA discrete populations of astrocytes and neurons in cocaine reinstatement after PrEP or ART+EcoHIV. Aim 3 will evaluate whether allopregnanolone administration reduces cocaine reinstatement and alters neuroimmune signaling. Together, these Aims are to expected define the mPOA as a mediator of drug seeking and immune state following treatment with antiretrovirals, and further to identify hormonal strategies to suppress relapse in individuals taking PrEP or with virally suppressed HIV infection.