Epigenetic Reprogramming in HIV-Associated Cardio-Vascular Disease

摘要 艾滋病毒感染与动脉粥样硬化和心血管疾病（CVD）的风险增加有关。这种风险 即使通过联合抗逆转录病毒治疗将艾滋病毒载量抑制到无法检测的水平，也不会消退 （cART）。尚未完全了解cART治疗受试者中CVD持续风险的原因。虽然cART 代谢效应可能会导致这种过度风险，但这不是唯一或主要的原因，因为新的 抗逆转录病毒药物的产生减少了代谢副作用， 也增加了动脉粥样硬化性心血管疾病的风险。我们和其他人已经证明，一些病毒介导的 CVD风险可能涉及高密度脂蛋白结构和胆固醇逆向转运的失调 功能另一个影响因素是先天免疫系统的持续激活，可能是由于 破坏肠道屏障和细菌渗漏。然而，目前尚不清楚为什么这些因素不 在艾滋病毒复制被cART降低到检测不到的水平后，我们假设 艾滋病相关动脉粥样硬化是由两个打击机制引起的：艾滋病病毒在早期复制，未经治疗， 感染阶段诱导骨髓细胞的先天记忆，增加其对TLR配体的反应性， 这在cART启动后持续存在，因此即使是低水平的细菌移位通过不完全的 恢复的肠粘膜导致持续的炎症和CVD。这一假设是基于出版的 显示单核细胞暴露于真菌细胞壁β-葡聚糖后训练的先天免疫的文献，以及 我们的初步证据表明，HIV Nef驱动人类单核细胞的训练免疫。在这里，我们建议测试 这一假设使用的血液和内窥镜样本来自一项干预性试验， 本提案的方案设计/方案执行指标（目标1）。在这项试验中，接受稳定cART的HIV阳性队列被随机分配至安慰剂组或 替度鲁肽，一种胰高血糖素样肽2（GLP-2）类似物，可增加肠道上皮屏障的紧密性， 减少肠漏。我们将采用先进的表观基因组学、转录组学和细胞生物学方法 以测试先天免疫记忆程序的激活是否与 动脉炎症和冠状动脉粥样硬化性疾病，以及GLP-2治疗是否逆转训练的 记忆在目标2中，我们将通过小鼠模型实验补充人类队列研究， 确定驱动持久先天免疫记忆的特定病毒和宿主因素， 行动机制。拟议的研究将提供对HIV患者心血管疾病风险原因的机制性见解， 感染的受试者，并可能告知未来的治疗和预防策略，以减少心血管疾病， 人口

Abstract HIV infection is associated with increased risk for atherosclerosis and cardio-vascular disease (CVD). This risk does not subside even when HIV load is suppressed to undetectable levels by combined anti-retroviral therapy (cART). Reasons for persistent risk of CVD in cART-treated subjects are not fully understood. Although cART metabolic effects may drive some of this excess risk, this cannot be the only or the main reason, since new generation of anti-retroviral drugs have reduced metabolic side-effects, and cART-naïve HIV-infected subjects also have increased atherosclerotic CVD risk. We, and others, have shown that some of the virus-mediated CVD risk may involve dysregulation of high density lipoprotein structure and reverse cholesterol transport function. Another contributing factor is persistent activation of the innate immune system, presumably due to disruption of the gut barrier and bacterial leakage. However, it remains unclear why these factors do not subside after HIV replication had been brought down to undetectable levels by cART. We hypothesize that HIV-associated atherosclerosis is caused by a two-hit mechanism: HIV replication during the early, untreated phase of infection induces innate memory in myeloid cells increasing their responsiveness to TLR ligands, which persists after cART initiation, so that even low levels of bacterial translocation through the incompletely recovered gut mucosa lead to persistent inflammation and CVD. This hypothesis is based on published literature showing trained innate immunity after exposure of monocytes to fungal cell wall β-glucans, and on our preliminary evidence that HIV Nef drives trained immunity of human monocytes. Here, we propose to test this hypothesis using blood and endoscopic samples from an interventional trial conducted by one of the PD/PIs of this proposal (aim 1). In this trial, an HIV-positive cohort on stable cART is randomized to placebo or teduglutide, a glucagon-like peptide 2 (GLP-2) analog that increases the tightness of gut epithelial barrier and reduces intestinal leakage. We will use advanced epigenomic, transcriptomic and cell biology methods applied to monocytes from these subjects to test if activation of the innate immune memory program is associated with arterial inflammation and coronary atherosclerotic disease, and whether GLP-2 treatment reverses trained memory. In aim 2 we will complement the human cohort studies with experiments in mouse models to determine specific viral and host factors driving the long lasting innate immune memory, and identify their mechanisms of action. Proposed studies will provide mechanistic insight into causes of CVD risk in HIV- infected subjects and will likely inform future therapeutic and preventative strategies to reduce CVD in this population.