Alcohol & Metabolic Comorbidities in PLWHA; Evidence-Driven Interventions

摘要 在美国，长期饮酒是最常见和代价高昂的药物滥用形式 在艾滋病毒/艾滋病患者(PLWHA)中高度流行。抗逆转录病毒疗法(ART)已大大减少 艾滋病毒/艾滋病死亡率，艾滋病毒感染正在成为一种慢性疾病，代谢风险增加 胰岛素抵抗和糖尿病前期等并存疾病。慢性危险饮酒(审核分数≥5)为 也是这些合并症的风险因素。猴慢性酗酒(CBA)的实验研究 免疫缺陷病毒(SIV)感染(CBA/SIV)的雄性恒河猴(经ART治疗和幼稚)有 研究表明，功能障碍的骨骼肌(SKM)与血糖调节受损有关，尽管正常 空腹血糖。该UH2 UH3应用程序建议利用我们正在进行的翻译研究(第60页 AA009803；PI：Molina)路易斯安那州的老龄化：免疫衰老、艾滋病毒和社会环境因素(活着) 在一群接受护理的成人PLWHA中进行研究，将我们在猕猴模型中的发现转化为结论。我们提出了一个 结合两个阶段的横断面和前瞻性研究来检验预测较高比例的 具有审计≥5的亚临床空腹血糖异常的PLWHA将出现口服糖耐量受损。 我们假设，代谢紊乱的SKM和线粒体内稳机制的丧失是 这种代谢共病背后的重要机制。在UH2阶段提出的研究旨在 验证这一“干预前”假说。在UH3阶段提出的研究将检验SKM的假设 有氧运动可以增强(或恢复)代谢功能和线粒体动态平衡， 改善血糖控制。将被测试的假设是基于从我们的 CBA/SIV猕猴代谢紊乱的综合特征及初步发现 从PLWHA收集的数据中期分析获得，该数据被招募到我们的Alive研究。我们的双向 翻译方法确保了我们来自非人类灵长类动物的发现与人类状况的相关性。 拟议的研究将由一个具有成熟专业知识的跨学科调查小组进行 酒精对SIV/HIV感染宿主代谢合并症影响的研究进展。这个项目将 受益于丰富的科学环境和卓越的实验和分析资源核心 LSUHSC综合酒精研究中心。预期的结果应该会产生深远的影响 关于减少患新陈代谢合并症的风险，这些合并症对健康造成重大负担 照顾PLWHA。这些研究结果将有助于更大规模的干预措施促进更严格的 确定可能受益于预防措施的高危PLWHA的方法 活动和改变行为，从而改善健康，提高生活质量，并可能减少危险 酗酒。

Abstract Chronic alcohol consumption is the most common and costly form of substance abuse in the United States and is highly prevalent in persons living with HIV/AIDS (PLWHA). Antiretroviral therapy (ART) has greatly reduced HIV/AIDS mortality, and HIV infection is emerging as a chronic disease with enhanced risk for metabolic comorbidities like insulin resistance and prediabetes. Chronic hazardous alcohol drinking (AUDIT score ≥5) is also a risk factor for these comorbidities. Our studies in chronic binge alcohol (CBA) administered simian immunodeficiency virus (SIV)-infected (CBA/SIV) male rhesus macaques (ART-treated and -naïve) have shown that dysfunctional skeletal muscle (SKM) is associated with impaired glucose regulation despite normal fasting glycemia. This UH2UH3 application proposes to leverage our ongoing translational study, (P60 AA009803; PI: Molina) Aging in Louisiana: Immunosenescence, hiV, & socioEnvironmental factors (ALIVE) Study in a cohort of in-care adult PLWHA to translate our findings from the macaque model. We propose a combined two phase cross-sectional and prospective study to test the prediction that a higher proportion of PLWHA with AUDIT ≥5 with subclinical fasting dysglycemia will present with impaired oral glucose tolerance. We hypothesize that dysfunctional metabolic SKM and loss of mitochondrial homeostatic mechanisms are important mechanisms underlying this metabolic comorbidity. Studies proposed in the UH2 phase aim to validate this “preintervention” hypothesis. Studies proposed in the UH3 phase will test the hypothesis that SKM metabolic function and mitochondrial homeostasis can be enhanced (or restored) by aerobic exercise, improving glycemic control. The hypotheses to be tested are based on evidence derived from our comprehensive characterization of metabolic dysregulation in CBA/SIV macaques and on preliminary findings obtained from interim analysis of data collected from PLWHA recruited to our ALIVE study. Our bi-directional translational approach ensures relevance of our findings from non-human primates to the human condition. The proposed study will be conducted by an interdisciplinary team of investigators with established expertise on studies of the impact of alcohol on metabolic comorbidities in the SIV/HIV infected host. This project will benefit from the rich scientific environment, and outstanding Experimental and Analytical Resource Cores of the LSUHSC Comprehensive Alcohol Research Center. The expected results should have a profound impact on ameliorating the risk of developing metabolic comorbidities that impose a significant burden on the health care of PLWHA. These study results will serve to inform larger scale interventions promoting a more rigorous approach to identification of at-risk PLWHA that may benefit from preventive measures to increase physical activity and modify behavior leading to improved health, quality of life, and possibly decreased hazardous alcohol drinking.