David R. Gretch, MD, PhD
Associate Professor of Laboratory Medicine and Medicine; Director, Viral Hepatitis Laboratory
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The laboratory focuses on hepatitis C virus (HCV) infection in humans and the resulting clinical manifestations we refer to as hepatitis C disease. In the past, we provided leadership in molecular diagnostics and therapeutics. We also contributed to understanding the natural history of chronic hepatitis C disease syndromes, both hepatic and extrahepatic. Presently, we are focused on viral-host interactions, both in vivo and in vitro. The strategy is to study subjects over time and monitor both viral evolution and host immunity. The major dogma is that immunity drives viral evolution. We have discovered that in subjects progressing to severe disease, immunity often fails, and viral evolution occurs with minimal genetic evidence of selection. In fact, viral genomes show remarkable conservation of protein structure during severe disease, significantly more so than during mild disease, as evidenced by dramatically higher ratios of synonymous non-synonymous mutations during severe disease. To investigate the molecular basis for preservation of HCV primary amino acid sequence during severe disease, viral genes are cloned from well-characterized patients, viral proteins are expressed in vitro, and both biochemical and molecular functions are compared between disease classes. To better understand the role of immune pressure in hepatitis C (e.g., is it beneficial or harmful?), human studies query the temporal relationships between intrahepatic HCV replication, HCV genetic evolution, and virus-specific immune responses in both liver and blood. Molecular studies seek to define novel interactions between HCV genes and cellular targets and address basic mechanisms such as viral persistence and antiviral resistance. The primary goal of the laboratory is to bridge basic and clinical research, in a manner that results in improvements in the care of patients with chronic hepatitis C.