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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|Narayanan, Sowmya; Surette, Fionna A; Hahn, Young S (2016) The Immune Landscape in Nonalcoholic Steatohepatitis. Immune Netw 16:147-58|
|Lim, Sung In; Hahn, Young S; Kwon, Inchan (2015) Site-specific albumination of a therapeutic protein with multi-subunit to prolong activity in vivo. J Control Release 207:93-100|
|Giugliano, Silvia; Kriss, Michael; Golden-Mason, Lucy et al. (2015) Hepatitis C virus infection induces autocrine interferon signaling by human liver endothelial cells and release of exosomes, which inhibits viral replication. Gastroenterology 148:392-402.e13|
|Golden-Mason, Lucy; Hahn, Young S; Strong, Michael et al. (2014) Extracellular HCV-core protein induces an immature regulatory phenotype in NK cells: implications for outcome of acute infection. PLoS One 9:e103219|
|Brownell, Jessica; Bruckner, Jacob; Wagoner, Jessica et al. (2014) Direct, interferon-independent activation of the CXCL10 promoter by NF-?B and interferon regulatory factor 3 during hepatitis C virus infection. J Virol 88:1582-90|
|Labonte, Adam C; Tosello-Trampont, Annie-Carole; Hahn, Young S (2014) The role of macrophage polarization in infectious and inflammatory diseases. Mol Cells 37:275-85|
|Lee, Hai-Chon; Narayanan, Sowmya; Park, Sung-Jae et al. (2014) Transcriptional regulation of IFN-? genes in hepatitis C virus-infected hepatocytes via IRF-3·IRF-7·NF-?B complex. J Biol Chem 289:5310-9|
|Stone, Amy E L; Mitchell, Angela; Brownell, Jessica et al. (2014) Hepatitis C virus core protein inhibits interferon production by a human plasmacytoid dendritic cell line and dysregulates interferon regulatory factor-7 and signal transducer and activator of transcription (STAT) 1 protein expression. PLoS One 9:e95627|
|Golden-Mason, Lucy; Rosen, Hugo R (2013) Natural killer cells: multifaceted players with key roles in hepatitis C immunity. Immunol Rev 255:68-81|
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