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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要/摘要尽管有效，艾滋病毒感染者患心血管疾病（CVD）的风险仍增加抗逆转录病毒治疗。新的证据表明，残留的持续性免疫失调会导致 HIV 人群的 CVD 风险。此外，代谢紊乱包括胰岛素抵抗、血脂异常和内脏肥胖增加在艾滋病毒感染者中很常见，并且也会显着导致心血管疾病的发生风险。本次资助申请的关键假设是 CCR2 和 CCR5 驱动炎症巨噬细胞和 T- 细胞进入包括动脉内膜在内的组织，导致动脉粥样硬化，并进入脂肪组织，导致胰岛素反抗。我们预计 CCR2 和 CCR5 趋化因子受体的双重拮抗作用将降低免疫激活，减少脉管系统炎症，减少脂肪组织炎症并减少胰岛素反抗。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、在 93 名成年男性和女性 HIV 感染者中进行了西尼基韦罗与安慰剂（比例为 2:1）的随机试验接受稳定 ART 治疗的 HIV-1 RNA 受到抑制的患者 CVD 风险增加，以 1) 确定双重治疗的影响 cenicriviroc 对动脉炎症和循环可溶性细胞标记物的 CCR2/CCR5 拮抗作用炎症和免疫激活的影响，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。该提案将利用 ACTG 的临床试验基础设施和广泛的科学专业知识 ACTG 内的合作研究人员和实验室。