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

通过 CCR2 和 CCR5 双重拮抗作用减少 HIV 感染者的动脉炎症并改善代谢健康

• 批准号: 10252755
• 负责人: Janet Lo
• 金额: $ 77.81万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-05 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10252755
• 关键词: AIDS clinical trial group; Acquired Immunodeficiency Syndrome; Adipose tissue; Adult; Antiviral Agents; Applications Grants; Arterial Intimas; Arteries; Atherosclerosis; Binding; Bioavailable; Biological; Biological Markers; Blood Vessels; CCL2 gene; CCL4 gene; CCR5 gene; Cell surface; Cells; Clinical Trials; Collaborations; Coronary heart disease; Development; Diabetes Mellitus; Disease; Double-Blind Method; Dyslipidemias; Gene Expression; Genes; HIV; HIV Infections; HIV-1; Health; Homing; Immune; Immune Targeting; Individual; Infiltration; Inflammation; Inflammatory; Infrastructure; Insulin Resistance; Intervention; Laboratories; Ligands; Mature T-Lymphocyte; Measures; Mediating; Metabolic; Metabolic Diseases; Obesity; Oral; PET/CT scan; Pathogenesis; Patients; Placebos; Population; RNA; Randomized; Randomized Clinical Trials; Research; Research Personnel; Residual state; Risk; Signal Transduction; Site; T-Cell Activation; T-Lymphocyte; Testing; Tissues; Tunica Intima; United States; Visceral; Woman; X-Ray Computed Tomography; antiretroviral therapy; cardiovascular disorder risk; chemokine; chemokine receptor; circulating biomarkers; coronary plaque; cytokine; effective intervention; immune activation; improved; in vivo; inflammatory marker; inhibitor/antagonist; insulin sensitivity; lipid biosynthesis; macrophage; men; monocyte; nonalcoholic steatohepatitis; novel; novel drug class; patient population; prospective; randomized trial; receptor; recruit; therapeutic candidate; therapeutically effective

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.

项目总结/摘要 艾滋病毒感染者患心血管疾病（CVD）的风险增加， 抗逆转录病毒疗法新出现的证据表明，残留的持续性免疫失调有助于 HIV人群中的CVD风险。此外，包括胰岛素抵抗、血脂异常和 内脏脂肪增多在HIV感染者中很常见，也是导致CVD过多的重要原因 风险 这项拨款申请的关键假设是，CCR 2和CCR 5驱动炎性巨噬细胞和T细胞， 细胞进入组织，包括动脉内膜，引起动脉粥样硬化，并进入脂肪组织，引起胰岛素 阻力我们预期CCR 2和CCR 5趋化因子受体的双重拮抗作用将降低免疫应答。 激活，减少脉管系统中的炎症，减少脂肪组织炎症和减少胰岛素 阻力为了验证我们的假设，我们提出了一个多中心安慰剂对照，双盲，24周长， 赛尼克韦罗与安慰剂（比例为2：1）在93名成年男性和女性HIV感染者中的随机试验， 抑制HIV-1 RNA对稳定ART的影响，这些ART增加了CVD风险，以1）确定双重 赛尼克韦罗对动脉炎症和循环可溶性和细胞标志物的CCR 2/CCR 5拮抗作用 和2）为了确定CCR 2/CCR 5双重拮抗作用对炎症和免疫活化的影响， CVC对胰岛素抵抗和脂肪组织炎症、基因表达及免疫细胞的影响。 该提案将利用ACTG的临床试验基础设施和 在ACTG内合作的研究人员和实验室。