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.
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|Lee, Hai-Chon; Sung, Sung-Sang J; Krueger, Peter D et al. (2013) Hepatitis C virus promotes T-helper (Th)17 responses through thymic stromal lymphopoietin production by infected hepatocytes. Hepatology 57:1314-24|
|Golden-Mason, Lucy; Rosen, Hugo R (2013) Natural killer cells: multifaceted players with key roles in hepatitis C immunity. Immunol Rev 255:68-81|
|Polyak, Stephen J; Ferenci, Peter; Pawlotsky, Jean-Michel (2013) Hepatoprotective and antiviral functions of silymarin components in hepatitis C virus infection. Hepatology 57:1262-71|
|Esser-Nobis, Katharina; Romero-Brey, Ines; Ganten, Tom M et al. (2013) Analysis of hepatitis C virus resistance to silibinin in vitro and in vivo points to a novel mechanism involving nonstructural protein 4B. Hepatology 57:953-63|
|Brownell, Jessica; Wagoner, Jessica; Lovelace, Erica S et al. (2013) Independent, parallel pathways to CXCL10 induction in HCV-infected hepatocytes. J Hepatol 59:701-8|
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