LSUHSC CARC RC1: Effects of Chronic Alcohol Abuse on HIV in the Genital Mucosal Environment Alcohol use disorders (AUD) are a significant health problem worldwide, especially among those at risk for or living with HIV. Women comprise 50% of the HIV-infected population worldwide; therefore, it is increasingly important to understand how co-morbidities, such as AUD, affect HIV acquisition and disease progression in women. As survival rates among women with HIV have increased dramatically due to anti-retroviral therapy (ART), the effects of aging, menopause, and hormonal loss on HIV disease are also highly relevant, yet understudied issues for women's health. The experimental control afforded by the SIV-infected rhesus macaque model provides an ideal setting to decipher the specific mechanisms by which chronic binge alcohol abuse (CBA) affects HIV acquisition and disease progression. Our previous studies identified key changes in the female reproductive tract (FRT) of macaques exposed to CBA, which are consistent with a more favorable environment for HIV transmission. These included an increased percentage of HIV/SIV T-cell targets in the vaginal submucosa, increased presence of inflammatory cells, and alterations to the microbiota. Our observations have led us to hypothesize that CBA: (1) Enhances the acquisition and early replication of HIV following vaginal exposure by changing the function and distribution of submucosal immune cells and reducing the innate defenses of the genital compartment; and (2) Increases viral replication in tissue reservoirs specifically in the genital tract, resulting in the persistence and shedding of HIV within the reproductive tract; and (3) Exacerbates viral replication and shedding in the genital compartment of gonadal hormone-deficient females. Using rhesus macaque females exposed to either CBA or isocaloric sucrose (SUC) and SIV, we will evaluate these hypotheses in three aims. (1) We will evaluate the effects of CBA on the FRT through assessments of innate defense molecules and analysis of mucosal cell phenotypes. Subsequently, females will be inoculated with SIV using a multiple low-dose vaginal exposure protocol, to determine if CBA directly increases susceptibility to vaginal infection in females. (2) We will evaluate viral reservoirs in FRT tissue and draining lymph nodes to compare SIV levels and track founder viral genotypes in CBA and SUC animals over the course of ART. Additionally, this aim will evaluate vaginal fluid samples obtained from a clinical cohort of HIV-infected ART-treated women to translate and validate the results obtained from rhesus macaques in humans with AUD. (3) We will evaluate the combined effects of CBA and surgically-induced menopause on SIV disease and viral replication in the FRT of chronically-infected, ovariectomized macaques exposed to CBA/SUC. The results from these studies will aid in deciphering key mechanisms involved in transmission and genital HIV shedding in a high-risk female population that abuses alcohol, and thus guide the development of targeted interventions that can prevent HIV transmission and disease progression in the context of AUD.
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