Hepatitis C virus (HCV) infection is a major public health concern affecting approximately 3% of the worid's population (1). HCV persists in up to 80% of people infected (2), and chronic infection can lead to progressive liver disease including cirrhosis and hepatocellular carcinoma. HCV-related liver disease is the single leading indication for liver transplantation throughout the worid. Although new therapies have improved the rates of sustained response, a large proportion of patients fails to respond to antiviral treatment or develop significant drug toxicity, thus remaining at risk for disease progression. A subset of individuals is able to mount effective anti-HCV immune responses, and compelling data underscore the importance of the quality and nature of the CTL response in mediating spontaneous and treatment-induced clearance of HCV. An understanding of HCV-host interactions is required to combat this virus and to develop improved therapies. We propose the following inter-related aims:
Specific Aim 1 : To comprehensively investigate the role ofthe T cell immunoglobulin and mucin domain-containing protein-3 (Tim-3)/galectin-9 pathway in conferring protective immunity versus persistence in acute and chronic HCV infection.
Specific Aim 2 : To investigate the effect of manipulating multiple costimulatory/coinhibitory pathways that regulate immune exhaustion and failure of HCV-specific CTLs, define the extent of polyfunctional restoration, and identify the distinct intracellular mechanisms.
Specific Aim 3 : Determine the phenotypic and fimctional aspects of natural killer T (NKT) cells that can be manipulated in order to enhance anti-HCV efficacy.

Agency
National Institute of Health (NIH)
Type
Research Program--Cooperative Agreements (U19)
Project #
5U19AI066328-10
Application #
8712324
Study Section
Special Emphasis Panel (ZAI1)
Project Start
Project End
Budget Start
Budget End
Support Year
10
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Colorado Denver
Department
Type
DUNS #
City
Aurora
State
CO
Country
United States
Zip Code
80045
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