The overall objective of this Mentored Patient-Oriented Research Career Development Award is to integrate the candidate's background in patient-oriented research with new training in molecular virology to understand the molecular basis of interferon response in the treatment of chronic hepatitis C (HCV). Hepatitis C infection is the leading cause of clinical liver disease in the U.S. Interferon treatment responses vary greatly in HCV infection, and are particularly poor in HIV-infected and African-American patients. In this grant, the candidate will examine the effect of interferon on viral kinetics of HCV during therapy in patients representing a range of clinical scenarios. We hypothesize that sequence variation in the NS5A region and the diversity of HCV quasispecies influence the 1st phase slope (decline) induced by interferon therapy. To test this hypothesis, we will closely examine the viral kinetics at early time points in HCV-infected patients with and without HIV among an equal number of African Americans and Caucasians to identify those with rapid vs. slower initial interferon responses. Next, using molecular cloning and sequencing techniques, we will determine the complexity and diversity of the HCV genome prior to initiation of interferon therapy and at these same early time points after initial interferon dosing. Sequencing the entire NS5A region of each clone will be used to correlate specific mutations with 1st phase slope and with genomic complexity and diversity using bioinformatics techniques. Characterization of early viral kinetics and NS5A molecular changes during interferon therapy in populations that have different response rates to interferon therapy may provide novel insights into mechanisms of interferon action with the goal of improving treatment responses. Combining in-depth training in molecular virology with the candidate's strong background in patient-oriented research, HIV medicine, and hepatology will prepare her to become an independent investigator in the area of HIV/HCV co-infection.
