LSUHSC CARC RC2: Alcohol & Metabolic Dysregulation in SIV/HIV; muscle & adipose mechanisms Alcohol use disorders (AUD) are common in people living with HIV/AIDS (PLWHA). Increased survival resulting from antiretroviral therapy (ART), has elevated the risk for comorbid conditions, arising from both chronic alcohol consumption and HIV infection, including myopathy, insulin resistance, prediabetes, and lipodystrophy. Female PLWHA are increasingly reaching and living beyond menopause (occurring at earlier ages) and are afflicted with greater risk for age-associated chronic diseases. Our studies in the chronic binge alcohol (CBA) consuming non-ART simian immunodeficiency virus (SIV)-infected (CBA/SIV) male non-human primates (NHP) showed that decreased and dysfunctional skeletal muscle (SKM) mass is a critical determinant of time to end-stage disease and that acceleration of SAIDS wasting is associated with accentuated SKM inflammation, profound depletion of anti-oxidant capacity, increased proteasome activity, and decreased myoblast differentiation potential. Preliminary findings have identified that CBA/SIV/ART macaques present with lipodystrophy that is reflected in an increased % abdominal adipose tissue deposition, decreased circulating levels of adiponectin, increased adipose tissue inflammatory cytokine and resistin expression, which we hypothesize contributes to decreased insulin sensitivity. The impact of CBA on SIV/ART associated dysregulation of SKM functional phenotype and lipodystrophy, and its interaction with gonadal hormones has not been examined in female NHP. The consequences of ovarian hormone (especially estrogen) loss on metabolic regulation have not been systematically explored in a research or a clinical setting. The proposed studies Alcohol & Metabolic Dysregulation in SIV/HIV; Muscle & Adipose Mechanisms, using a unique experimental approach integrating pre-clinical and clinical in vivo studies with mechanistic in vitro approaches, will be the first to explore the interaction of SKM and adipose tissue in the progression of metabolic dysfunction in CBA/SIV/ART+ female NHP and PLWHA. We hypothesize that SKM and adipose dysfunctional phenotypes will be further accentuated with loss of gonadal function through exacerbation of CBA- and SIV-associated inflammation.
Three Specific Aims test the predictions that dysfunctional SKM phenotype and lipodystrophy precede a detectable decrease in whole body insulin sensitivity, are accentuated by CBA, and further exacerbated by the loss of estrogen following ovariectomy (OVX). Clinical studies will examine whether the incidence of decreased lean body mass, muscle strength, lipodystrophy, and prediabetes are more frequent in female PLWHA with AUD, and accentuated post- menopause. The expected results will have a profound impact on the identification of the underlying mechanisms of CBA (or AUD)-associated insulin resistance in SIV/HIV subjects and the impact of estrogen loss on their severity. Furthermore, they will identify possible targets for therapeutic interventions to ameliorate HIV/ART associated metabolic derangements.
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