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: 8790399
• 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/8790399
• 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）：随着患者的寿命更长，非辅助事件已成为发病率和死亡率的主要原因。慢性HIV感染的特征是持续性炎症和免疫激活状态。慢性炎症可能会导致非AIDS疾病的发展（包括心血管疾病和脆弱），从而导致人体对组织损伤的正常反应和促进组织纤维化的正常反应，而不是正常的伤口愈合。纤维化可能是HIV感染者（HIV+）患者端机疾病的常见前体，但是纤维化标记与临床疾病的标记之间的关联是研究的，并且可以预防和治疗纤维化疾病的疗法 缺乏艾滋病毒+人。候选人的背景和职业发展：我是一名医师科学家，其研究重点是理解与炎症相关的艾滋病毒感染和抗逆转录病毒疗法（ART）的新型疗法的病理生理学。作为早期的调查员，我的长期目标是过渡到独立性并成为我领域的领导者。为此，我的短期目标包括进行高质量的，面向患者的研究（请参阅研究策略）并获得必要的额外培训。我有传染病的经验和培训以及HIV临床试验的设计和行为。但是，对艾滋病毒中炎症相关疾病的研究需要了解正常和病理免疫和生理过程，包括用于确定疾病机制的实验室技术。同样，尽管我拥有临床研究学位的科学硕士学位，但先进的数据分析和统计技能将帮助我成为独立的研究者。在K23奖项期间，我概述了正式的教学课程以及正常免疫学和生理学教程的结合，炎症相关疾病的病理生理学，实验室科学和高级数据分析。我还召集了一群具有HIV临床试验，转化研究，Viro免疫学，内分泌学和代谢方面的专业知识的导师。指导，教学培训和强大的研究愿景的这种结合将有助于我向独立过渡。研究建议：拟议的项目将通过HIV状态提供对循环纤维化标记的新描述，定义了纤维化循环标记与最终器官疾病（包括免疫功能）的临床估计之间的关联，并测试了创新的抗纤维化治疗。具体而言，我的目标是评估HIV+中纤维化标记与HIV+的最终器官疾病与HIV参与者之间的关系。纤维化是一种转化的生长因子-B1（TGF-B1）介导的过程，导致受伤组织中的透明质酸（HA）沉积。 TGF-B1和HA水平与HIV以外的炎症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。但是，尚不清楚TGF-B1和HA是否可以预测HIV+患者的非肝病严重程度。在控制混杂因素后，使用MACS血样，将测量TGF-B1和HA水平，并与临床疾病估计（包括肌肉质量，骨密度和动脉粥样硬化斑块负担）相关。我们假设1）HIV+中的TGF-B1和HA水平将高于HIV-参与者，而2）TGF-B1和HA水平将与所有参与者的最终器官疾病严重程度呈正相关，但是在HIV+参与者中，关联将更强。 2。评估纤维化循环标记，免疫激活和HIV+ MAC参与者中ART的免疫重建。淋巴组织纤维化发生在HIV感染的早期，可以防止ART上的CD4+ T细胞恢复，但是尚未描述纤维化，CD4+ T细胞计数与T细胞激活之间的关系。使用案例控制设计，将通过MAC样品来测量循环TGF-B1，HA和CD8+CD38+HLA-DR+T细胞计数，并在控制混杂因子后与免疫学反应者和非反应者之间的ART进行了比较。我们假设非反应者的TGF-B1，HA和激活的CD8+ T细胞水平比响应者更高。 3。为了评估telmisartan对艾滋病毒+患者最终器官疾病的纤维化和炎症性贡献者的影响。 Telmisartan是一种血管紧张素受体阻滞剂，PPAR-G激动剂批准用于治疗必需高血压。 Telmisartan改善了HIV种群中炎症和纤维化的标志。艾滋病临床试验小组研究A5317 telmisartan对HIV+患者最终器官疾病的纤维化和炎症性贡献者的影响，对ART（Lake，PI）进行了良好控制，是研究者发射的，两周臂，48周，随机（2：1），，供应Dose dose dose telemisartan in dretmisartan in preteD hiv invection。我们假设Telmisartan将改善HIV+患者的纤维化，炎症和免疫激活的淋巴结纤维化，皮下脂肪组织纤维化以及血液和组织标记（与对照组相比）。这将是第一个评估端骨对HIV+患者纤维化的影响的研究。