Reducing Arterial Inflammation and Improving Metabolic Health by Dual CCR2 and CCR5 Antagonism in People Living with HIV

项目摘要/摘要 艾滋病毒感染者增加了心血管疾病(CVD)的风险，尽管有效 抗逆转录病毒治疗。新出现的证据表明，残留的持续性免疫失调有助于 艾滋病毒人群中的心血管疾病风险。此外，代谢紊乱包括胰岛素抵抗、血脂异常和 内脏肥胖症在艾滋病毒携带者中很常见，也是过量心血管疾病的重要原因 风险。 这项拨款申请的关键假设是CCR2和CCR5驱动炎性巨噬细胞和T- 细胞进入组织，包括引起动脉粥样硬化的动脉内膜，以及进入脂肪组织，导致胰岛素 抵抗。我们预计CCR2和CCR5趋化因子受体的双重拮抗将降低免疫力 激活，减少血管系统的炎症，减少脂肪组织炎症和降低胰岛素 抵抗。为了检验我们的假设，我们提出了一项为期24周的多中心安慰剂对照、双盲、 93例成年HIV感染者与安慰剂(2：1比)的随机对照试验 抑制HIV-1RNA对稳定型ART患者心血管疾病风险的增加1)确定双重影响 Cenicriviroc拮抗CCR2/CCR5对动脉炎症及循环中可溶性和细胞标志物的影响 2)确定CCR2/CCR5双重拮抗作用的影响。 CVC对胰岛素抵抗和脂肪组织炎症、基因表达和免疫细胞的影响。 这项建议将利用ACTG的临床试验基础设施和 ACTG内部的合作调查人员和实验室。

PROJECT SUMMARY/ ABSTRACT People living with HIV infection have increased risk of cardiovascular disease (CVD), despite effective antiretroviral therapy. Emerging evidence show that residual persistent immune dysregulation contributes to CVD risk in the HIV population. In addition, metabolic disorders including insulin resistance, dyslipidemia and increased visceral adiposity are common in people with HIV and also contribute significantly to excess CVD risk. The key hypothesis of this grant application is that CCR2 and CCR5 drive inflammatory macrophages and T- cells into tissues including arterial intima causing atherosclerosis, and into adipose tissue causing insulin resistance. We expect that dual antagonism of CCR2 and CCR5 chemokine receptors will reduce immune activation, reduce inflammation in the vasculature, reduce adipose tissue inflammation and reduce insulin resistance. To test our hypotheses, we propose a multicenter placebo-controlled, double-blind, 24-week long, randomized trial of cenicriviroc vs. placebo (in 2:1 ratio) in 93 adult men and women living with HIV with suppressed HIV-1 RNA on stable ART who have increased CVD risk to 1) determine the impact of dual CCR2/CCR5 antagonism with cenicriviroc on arterial inflammation and circulating soluble and cellular markers of inflammation and immune activation and 2) To determine the impact of dual CCR2/CCR5 antagonism with CVC on insulin resistance and adipose tissue inflammation, gene expression, and immune cells. This proposal will leverage the clinical trial infrastructure of the ACTG and the extensive scientific expertise of collaborating investigators and laboratories within the ACTG.