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

描述（由申请人提供）：随着艾滋病毒感染者的寿命延长，非艾滋病事件已成为发病和死亡的主要原因。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使身体对组织损伤的正常反应失调和促进组织纤维化而不是正常伤口愈合而导致非AIDS疾病（包括心血管疾病和虚弱）的发展。纤维化可能是HIV感染者（HIV+）终末器官疾病的常见前兆，但纤维化标志物与临床疾病之间的相关性尚未得到充分研究，预防和治疗纤维化疾病的疗法 艾滋病病毒携带者缺乏。候选人的背景和职业发展：我是一名医生科学家，其研究重点是了解HIV感染和抗逆转录病毒治疗（ART）的炎症相关代谢并发症的病理生理学并开发新疗法。作为一名早期研究员，我的长期目标是过渡到独立，并成为我所在领域的领导者。为了实现这一目标，我的短期目标包括进行高质量的，以患者为导向的研究（见研究策略），并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性免疫和生理过程，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研究者。对于K23奖期间，我已经概述了正规的教学课程和指导教程在正常的免疫学和生理学，炎症相关疾病的病理生理学，实验室科学和先进的数据分析相结合。我还召集了一批在艾滋病毒临床试验、转化研究、病毒免疫学、内分泌学和代谢方面具有专长的导师。这种导师制，教学培训和强大的研究愿景的结合将促进我向独立的过渡。研究提案：拟议的项目将通过HIV状态提供循环纤维化标志物的新描述，定义纤维化循环标志物与终末器官疾病（包括免疫功能）的临床估计之间的关联，并测试创新的抗纤维化疗法。具体来说，目标1。评估多中心艾滋病队列研究（MACS）中HIV+和HIV-受试者中纤维化循环标志物与终末器官疾病之间的关系。纤维化是转化生长因子-b1（TGF-β 1）介导的过程，其导致透明质酸（HA）在损伤组织中沉积。TGF-β 1和HA水平与HIV以外的炎性疾病中的组织纤维化严重程度相关，HA与HIV中的肝纤维化相关。然而，目前尚不清楚TGF-β 1和HA是否可以预测HIV+患者的非肝脏疾病严重程度。使用MACS血液样本，测量TGF-b1和HA水平，并在控制混杂因素后与临床疾病估计值（包括瘦肌肉质量、骨密度和动脉粥样硬化斑块负荷）相关。我们假设：1）HIV+受试者的TGF-β 1和HA水平高于HIV-受试者，2）所有受试者的TGF-β 1和HA水平均与终末器官疾病严重程度呈正相关，但在HIV+受试者中相关性更强。2.评估HIV+ MACS受试者ART中纤维化循环标志物、免疫激活和免疫重建之间的关系。类扁桃体组织纤维化发生在HIV感染的早期，可以阻止ART中的CD 4 + T细胞恢复，但纤维化标志物、CD 4 + T细胞计数和T细胞活化之间的关系尚未被描述。使用病例对照设计，将从MACS样本中测量循环TGF-β 1、HA和CD 8 + CD 38 +HLA-DR+ T细胞计数，并在控制混杂因素后比较ART免疫应答者和非应答者。我们假设无应答者比应答者具有更高的TGF-β 1、HA和活化的CD 8 + T细胞水平。3.评估替米沙坦对ART控制良好的HIV+患者终末器官疾病的纤维化和炎症贡献者的影响。替米沙坦是一种血管紧张素受体阻滞剂和PPAR-g激动剂，获批用于治疗原发性高血压。替米沙坦改善HIV-人群的炎症和纤维化标志物。AIDS临床试验组研究A5317替米沙坦对ART控制良好的HIV+患者中终末器官疾病的纤维化和炎症贡献因素的影响（Lake，PI）是一项研究者启动的、双组、48周、随机化（2：1）、开放标签试验，旨在评价标准剂量替米沙坦对治疗的HIV感染的影响。我们假设替米沙坦将改善接受抑制性ART的HIV+患者的淋巴结纤维化、皮下脂肪组织纤维化以及纤维化、炎症和免疫激活的血液和组织标志物（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.