Alcohol & Metabolic Comorbidities in PLWHA; Evidence-Driven Interventions

摘要 慢性酒精消费是美国最常见和最昂贵的药物滥用形式， 在艾滋病毒/艾滋病感染者（PLWHA）中非常普遍。抗逆转录病毒疗法（ART）大大减少了 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， 胰岛素抵抗和前驱糖尿病等并发症。慢性危险饮酒（AUDIT评分≥5）是 也是这些合并症的一个风险因素。我们的研究在慢性酗酒（CBA）给予猿猴 免疫缺陷病毒（SIV）感染（CBA/SIV）的雄性恒河猴（ART治疗和未经治疗） 显示功能障碍的骨骼肌（SKM）与葡萄糖调节受损相关，尽管正常的 禁食本UH 2UH 3申请建议利用我们正在进行的翻译研究（P60 AA 009803; PI：Molina）路易斯安那州的老龄化：免疫衰老，hiV和社会环境因素（ALIVE） 在护理成人PLWHA队列中进行研究，以将我们的发现转化为猕猴模型。我们提出了一个 结合两个阶段的横截面和前瞻性研究，以检验预测， AUDIT ≥5且伴有亚临床空腹血糖异常的PLWHA将表现为口服葡萄糖耐量受损。 我们假设代谢性SKM功能障碍和线粒体稳态机制的丧失是 这种代谢合并症的重要机制。UH 2阶段提出的研究旨在 验证这个“预先干预”的假设。UH 3阶段提出的研究将检验SKM 代谢功能和线粒体稳态可以通过有氧运动来增强（或恢复）， 改善血糖控制。要检验的假设是基于我们的证据， CBA/SIV猕猴代谢失调的综合特征和初步发现 从我们的ALIVE研究招募的PLWHA收集的数据的中期分析中获得。我们的双向 翻译方法确保了我们从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既定专业知识的跨学科研究人员小组进行 研究酒精对SIV/HIV感染宿主代谢共病的影响。该项目将 受益于丰富的科学环境，以及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 改善对健康造成重大负担的代谢合并症的风险 照顾PLWHA。这些研究结果将有助于为更大规模的干预措施提供信息， 确定可能受益于预防措施的高危艾滋病毒/艾滋病感染者的方法， 活动和改变行为，从而改善健康，生活质量，并可能减少危险 饮酒。

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.