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.
HIV infection causes inflammation in the body that can lead to fibrosis (or scarring) of the organs, and may contribute to increased risk for or early onset of health problems such as heart disease, memory loss and loss of bone strength. Fibrosis may also prevent T cell increases following initiation of antiretroviral therapy. The projects outlinedin this proposal aim to understand organ fibrosis in the setting of HIV infection (including risk factors for, consequences of and potential treatments for fibrosis), information which will be critical to our ability to prevent and treat inflammation- and fibrosis-related disease in HIV+ persons.
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