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

项目总结 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患者能够实现 长期缓解存活至中老年。这种增加的存活率导致了 与艾滋病毒和/或抗逆转录病毒治疗有关的各种合并症，包括代谢性疾病、艾滋病定义的癌症以及 神经认知障碍。尤其是关于代谢性疾病，脂肪营养不良与 早期的抗逆转录病毒疗法已经被体重增加和脂肪组织改变的发生率增加所取代 服用较新的抗逆转录病毒药物制剂的患者，其功能以及患2型糖尿病的风险增加。建议 机制包括艾滋病毒引起的肠道完整性破坏和微生物成分移位，这些微生物成分可以 影响组织靶点，如内脏(特别是大网膜)脂肪组织，以产生慢性 全身性炎症是新陈代谢功能障碍的一个众所周知的原因。另一个影响的主要问题 艾滋病患者的大量人口是肥胖和糖尿病的全球流行，这也影响了 人们在艾滋病诊断和启动抗逆转录病毒治疗之前。因此，肥胖和糖尿病前期正日益成为一种 艾滋病患者的既往状况，这是我们总体假设的基础 肥胖/代谢性疾病调节艾滋病毒感染参数和对抗逆转录病毒治疗的反应，并加剧不利 通过对全身炎症的相加或协同作用产生的代谢效应。深入调查…… 将先前存在的代谢性疾病与艾滋病毒和抗逆转录病毒药物的代谢共病联系起来的机制需要 使研究在人类群体中不可行的临床前模型。猴免疫缺陷病毒 (SIV)/SIV感染的非人类灵长类动物(NHP；恒河猴)是主要的临床前研究模型 艾滋病毒的获取、抗逆转录病毒治疗的效果和疫苗开发。NHP也是理想的实验系统 对先前存在的肥胖的调查，因为它显示出对西式饮食的肥胖反应 反映了人类的消费模式，因此是人类饮食诱导的内在转换模型 肥胖和代谢功能障碍。我们建议将这两个独特的NHP模型合并，以模拟 通过追求以下具体目标来解决我们的假设。 具体目标1.在SIV挑战期间测定瘦身和肥胖受试者的病毒和免疫学参数 以及后来的艺术。 具体目标2.在SIV期间对瘦身和肥胖受试者进行全面的系统代谢分析 挑战和后续艺术。 具体目标3.确定SIV感染瘦身和肥胖受试者在感染SIV前后的组织特异性差异 艺术。

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 With respect to metabolic disease in particular, the lipodystrophy associated with early ART regimes has been replaced by an increased incidence of weight gain and altered adipose tissue function as well as increased risk for type-2 diabetes in patients on newer ART formulations.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.