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

HIV 感染成人的炎症、纤维化和终末器官疾病

• 批准号: 8853808
• 负责人: Jordan E Lake
• 金额: $ 18.91万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-06-01 至 2019-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8853808
• 关键词: AIDS clinical trial group; Acquired Immunodeficiency Syndrome; Adipose tissue; Adult; Agonist; Angiotensin Receptor; Arterial Fatty Streak; Biopsy; Blood; Blood specimen; Bone Density; CD4 Positive T Lymphocytes; CD8B1 gene; Cardiovascular Diseases; Cell Count; Chronic; Cicatrix; Clinical; Clinical Research; Clinical Trials; Cohort Studies; Communicable Diseases; Data Analyses; Deposition; Development; Disease; Dose; Endocrinology; Essential Hypertension; Event; Fibrosis; Frequencies; Functional disorder; Goals; HIV; HIV Infections; HLA-DR Antigens; Healed; Health; Heart Diseases; Hyaluronic Acid; Immune; Immunologics; Immunology; Inflammation; Inflammatory; Injury; Intervention; Knowledge; L Cells; Laboratories; Lead; Life; Link; Liver Fibrosis; Lymphoid Tissue; Master of Science; Measures; Mediating; Memory Loss; Mentored Patient-Oriented Research Career Development Award; Mentors; Mentorship; Metabolic; Morbidity - disease rate; Organ; Outcome; Participant; Pathologic; Pathway interactions; Patients; Peripheral Blood Mononuclear Cell; Peroxisome Proliferator-Activated Receptors; Persons; Physicians; Physiological Processes; Physiology; Pilot Projects; Population; Prevention; Process; Randomized; Recovery; Research; Research Personnel; Risk; Risk Factors; Role; Sampling; Science; Scientist; Severities; Severity of illness; Staging; Statistical Data Interpretation; Stimulus; T-Cell Activation; T-Lymphocyte; Techniques; Testing; Tissues; Training; Transforming Growth Factors; Translational Research; Vision; Wound Healing; antiretroviral therapy; arm; body system; bone health; bone strength; career development; case control; design; early onset; experience; frailty; healing; immune activation; immune function; improved; inflammatory marker; injured; innovation; lymph nodes; mortality; muscle form; novel; open label; patient oriented research; prevent; public health relevance; reconstitution; response; skills; subcutaneous fibrosis; telmisartan; traditional therapy

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.

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。慢性艾滋病毒感染的特点是持续炎症和免疫激活状态。慢性炎症可能会导致身体对组织损伤的正常反应失调，并促进组织纤维化而不是正常的伤口愈合，从而导致非艾滋病疾病（包括心血管疾病和虚弱）的发展。纤维化可能是 HIV 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关联尚未得到充分研究，并且预防和治疗纤维化疾病的疗法 HIV+ 人群中缺乏。候选人的背景和职业发展：我是一名医师科学家，其研究重点是了解 HIV 感染的炎症相关代谢并发症和抗逆转录病毒治疗 (ART) 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、以患者为导向的研究（参见研究策略）并获得必要的额外培训。我在传染病以及艾滋病毒临床试验的设计和实施方面拥有经验和培训。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研究者。在 K23 奖励期间，我概述了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方面的正式教学课程和指导教程的结合。我还组建了一群在艾滋病毒临床试验、转化研究、病毒免疫学、内分泌学和新陈代谢方面拥有专业知识的导师。指导、教学培训和强大的研究愿景的结合将有助于我向独立的过渡。研究提案：拟议项目将通过 HIV 状态提供对循环纤维化标志物的新颖描述，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，我的目标是 1. 评估多中心艾滋病队列研究 (MACS) 中 HIV+ 和 HIV- 参与者的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-b1) 介导的过程，导致透明质酸 (HA) 在受损组织中沉积。 TGF-b1 和 HA 水平与 HIV 以外的炎症性疾病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，TGF-b1 和 HA 是否可以预测 HIV 阳性者的非肝病严重程度尚不清楚。在控制混杂因素后，将使用 MACS 血液样本测量 TGF-b1 和 HA 水平，并将其与临床疾病估计（包括瘦肌肉质量、骨密度和动脉粥样硬化斑块负荷）相关联。我们假设 1) HIV+ 参与者的 TGF-b1 和 HA 水平将高于 HIV-参与者，2) TGF-b1 和 HA 水平将与所有参与者的终末器官疾病严重程度呈正相关，但这种关联会更强HIV+参与者。 2. 评估 HIV+ MACS 参与者中纤维化循环标记物、免疫激活和 ART 免疫重建之间的关系。淋巴组织纤维化发生在 HIV 感染早期，并且可以阻止 ART 中 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得到描述。采用病例对照设计，从 MACS 样本中测量循环 TGF-b1、HA 和 CD8+CD38+HLA-DR+ T 细胞计数，并在控制混杂因素后对 ART 的免疫应答者和非应答者进行比较。我们假设无应答者的 TGF-b1、HA 和活化的 CD8+ T 细胞水平高于应答者。 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，被批准用于治疗原发性高血压。替米沙坦可改善 HIV 感染人群的炎症和纤维化标志物。艾滋病临床试验小组研究 A5317 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影响因素（Lake，PI）是一项由研究者发起、双组、为期 48 周的随机研究（2： 1)、标准剂量替米沙坦治疗 HIV 感染效果的开放标签试验。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血液和组织纤维化标志物、炎症和免疫激活（与对照相比）。这将是第一项评估替米沙坦对艾滋病病毒感染者纤维化影响的研究。