Inflammation, Fibrosis and End-Organ Disease in HIV-Infected Adults

描述(申请人提供)：由于感染艾滋病毒的患者寿命更长，非艾滋病事件已成为发病率和死亡率的主要原因。慢性HIV感染的特征是持续的炎症和免疫激活状态。慢性炎症可能通过促进机体对组织损伤的正常反应的失调，促进组织纤维化而不是正常的伤口愈合，从而促进非艾滋病疾病(包括心血管疾病和虚弱)的发展。纤维化可能是艾滋病毒感染者(HIV+)终末器官疾病的常见先兆，但纤维化标志物与临床疾病之间的联系尚未得到充分研究，预防和治疗纤维化疾病的治疗方法还不够深入 在HIV+中，缺乏人。候选人背景和职业发展：我是一名内科科学家，其研究重点是了解艾滋病毒感染和抗逆转录病毒疗法(ART)的炎症相关代谢并发症的病理生理学，并开发新的疗法。作为一名早期调查员，我的长期目标是过渡到独立，成为我所在领域的领导者。要做到这一点，我的短期目标包括进行高质量的、以患者为中心的研究(参见研究战略)和获得必要的额外培训。我在传染病和艾滋病毒临床试验的设计和实施方面有经验和培训。然而，对艾滋病毒炎症相关疾病的研究需要了解正常和病理的免疫和生理过程，包括确定疾病机制的实验室技术。同样，虽然我拥有临床研究的理学硕士学位，但先进的数据分析和统计技能将帮助我成为一名独立的调查员。在K23获奖期间，我概述了正规教学课程和辅导教程的组合，包括正常免疫学和生理学、炎症相关疾病的病理生理学、实验室科学和高级数据分析。我还召集了一群在艾滋病毒临床试验、转译研究、病毒免疫学、内分泌学和新陈代谢方面具有专业知识的导师。这种指导、说教训练和强烈的研究视野的结合，将促进我向独立的过渡。研究建议：拟议的项目将根据HIV状态提供循环纤维化标志物的新描述，确定循环纤维化标志物与终末器官疾病(包括免疫功能)的临床估计之间的联系，并测试一种创新的抗纤维化治疗方法。具体地说，我的目标是1。评估多中心艾滋病队列研究(MACS)中HIV+和HIV参与者中循环中的纤维化标志物和终末器官疾病之间的关系。纤维化是转化生长因子-β1(TGF-β1)介导的导致透明质酸(HA)沉积在损伤组织中的过程。在HIV以外的炎症性疾病中，TGF-β1和HA水平与组织纤维化严重程度相关，而在HIV中，HA与肝纤维化相关。然而，目前尚不清楚转化生长因子-β1和透明质酸能否预测HIV阳性患者的非肝病严重程度。使用MACS血液样本，在控制混杂因素后，将测量转化生长因子-β1和透明质酸水平，并将其与临床疾病估计(包括瘦肉量、骨密度和动脉粥样硬化斑块负荷)相关联。我们假设：1)在HIV+患者中，转化生长因子-β1和透明质酸水平将高于艾滋病毒携带者；2)在所有参与者中，转化生长因子-β1和透明质酸水平将与终末器官疾病的严重程度呈正相关，但在HIV+参与者中，这种相关性会更强。2.探讨HIV+MACS患者血液循环纤维化指标、免疫激活和免疫重建之间的关系。淋巴组织纤维化发生在HIV感染的早期，可以阻止抗逆转录病毒治疗后CD4+T细胞的恢复，但纤维化标志物、CD4+T细胞计数和T细胞激活之间的关系尚未描述。采用病例对照设计，在控制混杂因素后，从MACS样本中测量循环中的转化生长因子-β1、透明质酸和CD8+CD38+人类白细胞抗原-DR+T细胞计数，并对免疫应答者和抗逆转录病毒治疗无应答者进行比较。我们假设无应答者比应答者有更高的转化生长因子-β1、透明质酸和激活的CD8+T细胞水平。3.评估替米沙坦对经抗逆转录病毒疗法控制良好的HIV阳性患者的肝纤维化和炎性因素的影响。替米沙坦是一种血管紧张素受体阻滞剂和PPAR-g激动剂，被批准用于治疗高血压。替米沙坦可改善HIV感染者的炎症和纤维化指标。艾滋病临床试验小组研究A5317替米沙坦对控制良好的抗逆转录病毒疗法(莱克，PI)患者的终末器官疾病的纤维化和炎症因素的影响，这是一项由研究人员发起的、双臂、为期48周的随机(2：1)开放标签试验，研究标准剂量替米沙坦治疗艾滋病毒感染的效果。我们假设替米沙坦将改善抑制ART的HIV+患者的淋巴结纤维化、皮下脂肪组织纤维化以及血液和组织纤维化标记物、炎症和免疫激活(与对照组相比)。这将是第一项评估替米沙坦对HIV+患者纤维化影响的研究。

DESCRIPTION (provided by applicant): As patients are living longer with HIV, non-AIDS events have become major causes of morbidity and mortality. Chronic HIV infection is characterized by a state of persistent inflammation and immune activation. Chronic inflammation may contribute to the development of non-AIDS diseases (including cardiovascular disease and frailty) by precipitating dysregulation of the body's normal response to tissue injury and promoting tissue fibrosis instead of normal wound healing. Fibrosis may be a common precursor of end- organ disease in HIV-infected (HIV+) persons, but associations between markers of fibrosis and clinical disease are understudied, and therapies to prevent and treat fibrotic disease in HIV+ persons are lacking. CANDIDATE'S BACKGROUND AND CAREER DEVELOPMENT: I am a physician scientist whose research focuses on understanding the pathophysiology of and developing novel therapies for the inflammation- associated, metabolic complications of HIV infection and antiretroviral therapy (ART). As an Early Stage Investigator, my long-term goals are to transition to independence and become a leader in my field. To accomplish this, my short-term goals include conducting high-quality, patient-oriented research (see Research Strategy) and obtaining necessary additional training. I have experience and training in Infectious Diseases and the design and conduct of HIV clinical trials. However, the study of inflammation-related disease in HIV requires knowledge of both normal and pathological immunologic and physiologic processes, including laboratory techniques for determining mechanisms of disease. Similarly, while I have a Master of Science in Clinical Research degree, advanced data analysis and statistical skills will help me to become an independent investigator. For the K23 award period, I have outlined a combination of formal didactic coursework and mentored tutorials in normal immunology and physiology, the pathophysiology of inflammation-related disease, laboratory science and advanced data analysis. I have also assembled a group of mentors with expertise in HIV clinical trials, translational research, viro-immunology, endocrinology and metabolism. This combination of mentorship, didactic training and a strong research vision will facilitate my transition to independence. RESEARCH PROPOSAL: The proposed projects will provide a novel description of circulating fibrosis markers by HIV status, define associations between circulating markers of fibrosis and clinical estimates of end-organ disease (including immune function), and test an innovative anti-fibrotic therapy. Specifically, I aim 1. To assess relationships between circulating markers of fibrosis and end-organ disease in HIV+ and HIV- participants in the Multicenter AIDS Cohort Study (MACS). Fibrosis is a transforming growth factor-b1 (TGF-b1)-mediated process that leads to hyaluronic acid (HA) deposition in injured tissues. TGF-b1 and HA levels correlate with tissue fibrosis severity in inflammatory diseases other than HIV, and HA correlates with hepatic fibrosis in HIV. However, it is unknown whether TGF-b1 and HA can predict non-hepatic disease severity in HIV+ persons. Using MACS blood samples, TGF-b1 and HA levels will be measured and associated with clinical disease estimates (including lean muscle mass, bone density, and atherosclerotic plaque burden) after controlling for confounding factors. We hypothesize that 1) TGF-b1 and HA levels will be higher in HIV+ than HIV- participants, and 2) TGF-b1 and HA levels will be positively associated with end- organ disease severity in all participants, but the associations will be stronger in HIV+ participants. 2. To assess relationships between circulating markers of fibrosis, immune activation and immune reconstitution on ART in HIV+ MACS participants. Lymphoid tissue fibrosis occurs early in HIV infection and can prevent CD4+ T cell recovery on ART, but relationships between markers of fibrosis, CD4+ T cell counts and T cell activation have not been described. Using a case control design, circulating TGF-b1, HA and CD8+CD38+HLA-DR+ T cell counts will be measured from MACS samples and compared between immunologic responders and non-responders to ART after controlling for confounding factors. We hypothesize that non-responders will have higher TGF-b1, HA and activated CD8+ T cell levels than responders. 3. To assess the effects of telmisartan on fibrotic and inflammatory contributors to end-organ disease in HIV+ persons well controlled on ART. Telmisartan is an angiotensin receptor blocker and PPAR-g agonist approved for the treatment of essential hypertension. Telmisartan improves markers of inflammation and fibrosis in HIV- populations. AIDS Clinical Trials Group study A5317 Effects of Telmisartan on Fibrotic and Inflammatory Contributors to End-Organ Disease in HIV+ Patients Well Controlled on ART (Lake, PI), is an investigator-initiated, two-arm, 48-week, randomized (2:1), open label trial of the effects of standard dose telmisartan in treated HIV infection. We hypothesize that telmisartan will improve lymph node fibrosis, subcutaneous adipose tissue fibrosis and blood and tissue markers of fibrosis, inflammation and immune activation in HIV+ patients on suppressive ART (compared to control). It will be the first study to assess the effects of telmisartan on fibrosis in HIV+ persons.