Co-infection with hepatitis C virus (HCV) has emerged as a major cause of morbidity and mortality for persons living with HIV/AIDS. Epidemiologic studies clearly indicate that HIV/HCV co-infection is associated with enhanced HCV replication, increased fibrosis, and the development of liver disease. HIV also increases quasispecies diversity of HCV structural genes. However, non-structural regions of the HCV genome such as NS5B are subject to distinct selection pressures - purifying selection necessary to preserve enzymatic functions critical for viral replication, drug resistance mutations, and/or compensatory mutations - compared to structural genome regions. Despite the growing importance of NS5B as an emerging target of HCV therapy, limited data are available regarding its genotypic variability and phenotypic properties in the absence of directly acting therapies. To address this substantial gap in our understanding of HCV replication and pathogenesis, we propose a comprehensive analysis of NS5B genotypic, phenotypic, and biochemical variability in two well-characterized populations with HCV and/or HIV co-infection. Such studies are critical to facilitate the rational design and utilization of novel HCV therapies and significantly improve the clinical management and overall survival of persons with chronic HCV infection.

Public Health Relevance

The HCV NS5B polymerase is essential for viral replication and is subject to considerable selection pressure from the immune system, antiviral drugs, functional constraints, and secondary RNA structures. As polymerase inhibitors are developed and enter widespread clinical use, evaluating the impact of HIV co- infection and antiretroviral therapy - both of which impact HCV replication, HCV diversity, and/or liver disease progression - will be essential for increasing the overall efficacy of these new agents. Thus, we propose a comprehensive analysis of NS5B genotypic, phenotypic, and biochemical variability in two well-characterized populations with HCV and/or HIV co-infection.

Agency
National Institute of Health (NIH)
Type
Research Project (R01)
Project #
3R01GM105414-02S1
Application #
8919517
Study Section
AIDS Clinical Studies and Epidemiology Study Section (ACE)
Program Officer
Eckstrand, Irene A
Project Start
Project End
Budget Start
Budget End
Support Year
2
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Cincinnati
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
City
Cincinnati
State
OH
Country
United States
Zip Code
45221