Chronic hepatitis C and B are important and growing causes of morbidity and mortality in the United States. In particular, a disproportionate burden of mortality is borne by groups with specific disease susceptibilities. These include patients with HIV coinfection and patients undergoing liver transplantation for HCV and HBV-related complications, both of whom experience accelerated natural history of disease. The basis for these observations is not well understood, but an increasing number of plausible hypotheses have been suggested by our preclinical work. As with the original submission of this application in the first cycle of this grant, this proposal demonstrates the candidate's track record of productivity and lengthy commitment to patient-oriented research in viral hepatitis and his record of mentorship in the development of junior faculty and fellows embarking on clinical and translational research careers in liver disease. Over the past grant cycle, Dr. Chung has fully followed through on the original aims of the proposal, which were to (1) mentor fellows and junior faculty in initiation of patient-oriented research careers in the study of HCV disease in special populations; and (2) initiate innovative pilot clinical trials in HCV based on key observations from our mechanistic work. During the first cycle of this Award, Dr. Chung has mentored over 20 Fellows and junior faculty, and many have secured NIH or foundation funding. The focus of the next cycle of Dr. Chung's program will be to integrate advances in the continuum of translational investigation into the training of the next generation of clinical researchers. These include the creation of disease cohorts, genomic and other discovery surveys of these cohorts, identification of biomarkers and therapeutic targets, development of novel therapies, application of these therapies in first in man proof of concept studies, application of biomarkers for use in disease prognostication and modeling. In this regard, Aim 1, development of clinical prediction models and disease management algorithms that incorporate fundamental discoveries such as genetic markers, will be an important focus for young clinical investigators in the next grant cycle, as will creation of novel disease cohorts, such as those with HBV-HIV coinfection. In Aim 2, advances in discovery will be tested in the therapeutic arena. These advances include our mechanistic work defining the dependence of HCV on cholesterol intermediates and the efficacy of statins in the viral lifecycle, along with our discovery that a flavonoid, naringenin, has antiviral effects against HCV secretion. This work will form the basis for design of innovative pilot clinical trials, including studies of agents to prevet allograft HCV infection, the most important source of mortality in persons undergoing liver transplantation (LT). In this vein, the PI's role as Vice Chair of the ACTG Hepatitis Transformative Science Group (TSG) will also enable the initiation of junior investigators in several exciting proof of concept studies testing novel combinations of direct acting antiviral agents and statins against HCV in both HIV(-) and HIV(+) hosts. Similarly, the PI's participation with the MGH Translational Medicine Group (TMG) will also permit engagement of junior investigators in translational studies of early phase compounds in special populations such as post-LT HCV. Collectively, these studies will offer rich opportunities for clinical investigators t be mentored as they enter the highly interdigitated continuum of translational investigation. In so doing, it is anticipated by Dr. Chung that they will themselves mentor their own fellows and faculty, thereby creating a highly desirable multiplier effect. PUBLIC HEALTH RELEVANCE: The training of the next generation of clinical and translational investigators in liver disease will require concerted efforts to harness the explosion of knowledge that has been enabled by 21st century technologies. An effective approach must today incorporate a fundamental understanding of the process from creation of populations of patients with disease, to making genetic and other discoveries in these patients, to functionally decoding the basis for these discoveries, to developing treatments based on the understanding of these decoded targets, to applying these treatments and markers back to the original disease population, and finally understanding how these discoveries can make our clinical decisions more effective. We plan to apply these modern tenets of translational medicine to special populations of patients with chronic viral hepatitis, in so doing making important headway in halting or slowing disease progression in these particularly vulnerable groups.