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)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program--Cooperative Agreements (U19)
Project #
5U19AI066328-08
Application #
8380557
Study Section
Special Emphasis Panel (ZAI1-BP-M)
Project Start
Project End
Budget Start
2012-09-01
Budget End
2013-08-31
Support Year
8
Fiscal Year
2012
Total Cost
$225,083
Indirect Cost
$37,889
Name
University of Colorado Denver
Department
Type
DUNS #
041096314
City
Aurora
State
CO
Country
United States
Zip Code
80045
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