Cardiovascular Risk of Antiretroviral Therapy Drugs in HIV

HIV 抗逆转录病毒治疗药物的心血管风险

• 批准号: 10700275
• 负责人: Jasimuddin Ahamed
• 金额: $ 70.11万
• 依托单位: OKLAHOMA MEDICAL RESEARCH FOUNDATION
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-01 至 2027-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10700275
• 关键词: Acceleration; Acetylcysteine; Antiplatelet Drugs; Autopsy; Blood Platelets; Cells; Clinical; Communicable Diseases; Data; Dose; Etiology; Exhibits; Fibrosis; Foundations; Functional disorder; Goals; HIV; HIV antiretroviral; Heart; Heart failure; Human; In Vitro; Individual; Injections; Intervention; Investigation; Knock-out; Life Expectancy; Link; LoxP-flanked allele; Macrophage; Magnetic Resonance Imaging; Measures; Mediating; Membrane Transport Proteins; Mesenchymal; Mus; Myeloid Cells; Myocardial dysfunction; Organ; Patients; Persons; Pharmaceutical Preparations; Phenotype; Pilot Projects; Pirfenidone; Plasma; Platelet Activation; Play; Population; Prevention strategy; Process; Protease Inhibitor; Proteins; Publishing; Quality of life; Regimen; Research; Risk; Ritonavir; Role; Signal Transduction; Source; Sudden Death; Techniques; Tenofovir; Testing; Transforming Growth Factor beta; Transforming Growth Factors; Transgenic Mice; Transgenic Organisms; Xenograft procedure; antifibrotic treatment; antiretroviral therapy; cardiovascular disorder risk; cardiovascular risk factor; cell type; comorbidity; coronary fibrosis; effective intervention; improved; in vivo; inhibitor; innovation; mouse model; novel strategies; patient population; pharmacologic; potential biomarker; prevent; profibrotic cytokine; receptor; recruit; translational potential

PROJECT SUMMARY Although antiretroviral therapy drugs (ART) have prevented HIV propagation and increased life expectancy of people with HIV (PWH), the rate of sudden death in this population is 2-4-times higher than people without HIV. Autopsies have revealed cardiac fibrosis in half of this HIV patient population, a likely etiology for sudden death. The protease inhibitor class ART (PI-ART) is linked to cardiovascular risk in PWH, and it is plausible that ART can exacerbate the risk by inducing cardiac fibrosis. Our long-term goals are to determine the mechanism and the impact of ART-induced cardiac fibrosis in PWH, and to explore preventive strategies. Transforming growth factor β1 (TGFβ1) is a strong profibrotic cytokine and platelets contain ~100 times more TGFβ1 than other cells and are a major source of plasma TGFβ1 contributing to organ fibrosis. Higher plasma TGFβ1 levels and cardiac fibrosis are observed in HIV+ individuals, but whether ART further increases plasma TGFβ1 and cardiac fibrosis in PWH is not clear. In pilot studies, we observed that newer ART regimens, including PI-boosted dose of ritonavir (RTV) and tenofovir, activated platelets to release TGFβ1, which can be blocked by Ceefourin-1, a specific inhibitor of MRP4, a membrane transporter highly expressed in platelets from HIV patients. Injection of a PI-boosted dose of RTV in transgenic Tg26 HIV mice (which exhibit multiple HIV-associated comorbidities) increased cardiac fibrosis and diastolic dysfunction associated with the accumulation of CD206+ cells expressing αSMA in the heart, presumably macrophages. These results led to our central hypothesis that ART may activate platelets to release TGFβ1 via MRP4, which stimulates macrophages to undergo mesenchymal transition, inducing cardiac fibrosis. The objective of this application is to determine the mechanism by which different classes of ART induce platelet TGFβ1 release and identify the cell types to which TGFβ1 signals, leading to cardiac fibrosis. The following Specific Aims will address the objective: 1) Screen a panel of different classes of ART, alone and in combination, for induction of platelet release of TGFβ1 and identify the mechanisms of this process; 2) Determine whether contemporary ART-mediated TGFβ1 release via MRP4 induces cardiac fibrosis in vivo; 3) Determine whether TGFβ1 signaling in macrophages leads to mesenchymal transition and cardiac fibrosis. Our studies will clarify the mechanism of ART-induced TGFβ1 release from platelets and the cell types on which TGFβ1 signals, leading to cardiac fibrosis. We will use innovative techniques to evaluate platelet activation, measure plasma TGFβ1 levels, and assess cellular signaling and cardiac fibrosis in two murine models of HIV. Furthermore, our research will explore the translational potential for mitigating ART-induced cardiac fibrosis in HIV mice with anti-TGFβ1 and anti-fibrotic agents, such as Galunisertib or Pirfenidone. Our studies may also elucidate whether TGFβ1 could be a potential biomarker of underlying organ fibrosis in PWH. It may also lay the foundation for better mechanistic understanding and novel strategies for preventing comorbidities in PWH and fibrosis in other infectious diseases.

项目摘要 虽然抗逆转录病毒疗法（ART）可以防止艾滋病毒的传播，并增加预期寿命， 艾滋病毒感染者（PWH）的猝死率比没有艾滋病毒的人高2-4倍。 尸检显示，在一半的艾滋病毒患者中存在心脏纤维化，这可能是猝死的病因。 蛋白酶抑制剂类ART（PI-ART）与PWH的心血管风险相关， 会通过诱发心脏纤维化而加剧风险。我们的长期目标是确定机制和 ART诱导心脏纤维化对PWH的影响，并探讨预防策略。转化生长因子β1 (TGFβ1）是一种强的促纤维化细胞因子，血小板含有比其他细胞多100倍的TGFβ1，是一种促纤维化细胞因子。 血浆TGFβ1是器官纤维化的主要来源。高血浆TGFβ1水平和心脏纤维化 但是ART是否会进一步增加PWH患者的血浆TGFβ1和心脏纤维化， 不清楚在试点研究中，我们观察到较新的ART方案，包括PI加强剂量的利托那韦（RTV）和 替诺福韦，激活血小板释放TGFβ1，这可以被MRP 4的特异性抑制剂Ceefourin-1阻断， 一种在HIV患者血小板中高度表达的膜转运蛋白。注射PI加强剂量的RTV 在转基因Tg 26 HIV小鼠（表现出多种HIV相关的合并症）中，心脏纤维化增加， 与心脏中表达αSMA的CD 206+细胞蓄积相关的舒张功能障碍， 可能是巨噬细胞。这些结果导致了我们的中心假设，ART可能激活血小板释放 TGFβ1通过MRP 4刺激巨噬细胞进行间质转化，诱导心脏纤维化。 本申请的目的是确定不同类别的ART诱导血小板聚集的机制。 TGFβ1释放并识别TGFβ1信号传导的细胞类型，导致心脏纤维化。以下具体 目的将解决的目标：1）筛选一组不同类别的艺术，单独和组合， 诱导血小板释放TGFβ1，并确定这一过程的机制; 2）确定是否 当代ART介导的TGFβ1通过MRP 4释放诱导体内心脏纤维化; 3）确定是否 巨噬细胞中的TGFβ1信号传导导致间质转化和心脏纤维化。我们的研究将阐明 ART诱导TGFβ1从血小板释放的机制以及TGFβ1信号传导的细胞类型， 心脏纤维化我们将采用创新技术评估血小板活化，测量血浆TGFβ1， 水平，并评估两种HIV小鼠模型中的细胞信号传导和心脏纤维化。此外，我们的研究 将探索在HIV小鼠中用抗TGF β1减轻ART诱导的心脏纤维化的转化潜力， 抗纤维化剂，如Galunisertib或吡非尼酮。我们的研究也可能阐明TGFβ1是否可以 是PWH潜在器官纤维化的生物标志物。这也可能为更好的机械化奠定基础。 预防PWH合并症和其他感染性疾病纤维化的新策略。