Effect of obesity on HIV pathogenesis, antiretroviral therapy, and metabolic comorbidities

项目摘要 有效的抗逆转录病毒疗法（ART）的出现使数百万艾滋病毒感染者能够实现 长期缓解并存活至中老年。这种生存率的提高导致了 与HIV和/或ART相关的多种合并症，包括代谢疾病、AIDS定义的癌症，以及 神经认知障碍特别是关于代谢疾病，与代谢相关的脂肪营养不良是一种常见的疾病。 早期的抗逆转录病毒疗法已被体重增加和脂肪组织改变的发生率增加所取代 功能以及增加2型糖尿病的风险在新的ART制剂的患者。提出 其机制包括HIV诱导的肠道完整性的破坏和微生物成分的移位， 影响组织目标，例如内脏（特别是网膜）脂肪组织，以产生慢性 全身性炎症是代谢功能障碍的一个有据可查的原因。另一个影响到 艾滋病患者人数众多是肥胖和糖尿病的全球流行病， 因此，肥胖症和前驱糖尿病越来越多地成为艾滋病患者的一个危险因素。 艾滋病患者的预先存在的条件，是我们的整体假设的基础，即预先存在的 肥胖/代谢性疾病调节HIV感染参数和对ART的反应，并加重不良反应。 通过对全身性炎症的累加或协同作用而产生代谢效应。的深入调查 将既存代谢疾病与HIV和ART的代谢共病联系起来的机制需要 临床前模型，使研究在人群中不可行。猴免疫缺陷病毒 (SIV)/SHIV感染的非人灵长类动物（NHP;恒河猴）是研究的主要临床前模型 艾滋病毒感染，ART的影响和疫苗开发。NHP也是理想的实验系统， 对既存肥胖症的研究，因为它对西式饮食表现出致肥胖反应， 反映了人类的消费模式，因此是人类饮食诱导的内在转化模型 肥胖和代谢功能障碍。我们建议合并这两个独特的NHP模型，以模拟 我们的假设是通过追求以下具体目标来实现的。 具体目标1.测定SIV攻毒期间瘦型和肥胖型受试者的病毒和免疫学参数 后来的艺术。 具体目标2。在SIV期间对瘦型和肥胖型受试者进行全面的全身代谢分析 挑战和后续艺术 具体目标3。确定SIV感染的瘦型和肥胖型受试者在治疗前和治疗期间的组织特异性差异 条

PROJECT SUMMARY The advent of effective antiretroviral therapy (ART) has enabled millions of HIV-infected patients to achieve long-term remission and survival to middle and old age. This increased survival has resulted in development of a variety of comorbidities linked to HIV and/or ART, including metabolic disease, AIDS-defining cancers, and neurocognitive disorders. With respect to metabolic disease in particular, the lipodystrophy associated with early ART regimes has been replaced by an increased incidence of weight gain and altered adipose tissue function as well as increased risk for type-2 diabetes in patients on newer ART formulations. Proposed mechanisms include HIV-induced disruption of gut integrity and translocation of microbial components that can affect tissue targets such as visceral (particularly omental) adipose tissue to generate a state of chronic systemic inflammation that is a well-documented cause of metabolic dysfunction. Another major issue affecting the large population of people living with AIDS is the global epidemic of obesity and diabetes that also affects people prior to their AIDS diagnosis and initiation of ART. Thus, obesity and prediabetes are increasingly a pre-existing condition in people living with AIDS, and is the basis for our overall hypothesis that pre-existing obesity/metabolic disease regulates HIV infection parameters and response to ART and exacerbates adverse metabolic effects through additive or synergistic effects on systemic inflammation. The in-depth investigation of the mechanisms that link pre-existing metabolic disease with metabolic comorbidities of HIV and ART requires preclinical models that enable studies not feasible in human populations. Simian immunodeficiency virus (SIV)/SHIV-infected nonhuman primates (NHP; rhesus macaques) are the primary preclinical model for study of HIV acquisition, effects of ART, and vaccine development. NHPs are also the ideal experimental system for the investigation of pre-existing obesity as it exhibits an obesogenic response to a western-style diet that mirrors human consumption patterns and is thus an inherently translational model for human diet-induced obesity and metabolic dysfunction. We propose to merge these two unique NHP models to mimic the state of affairs in the human population and to address our hypothesis through pursuit of the following specific aims. Specific aim 1. Determine viral and immunological parameters in lean and obese subjects during SIV challenge and subsequent ART. Specific aim 2. Perform comprehensive systemic metabolic profiling in lean and obese subjects during SIV challenge and subsequent ART. Specific aim 3. Determine tissue-specific differences in SIV-infected lean and obese subjects before and during ART.