Hepatitis C virus (HCV) is remarkable at disrupting human immunity to establish chronic infection;it is a global health problem with limited treatment options and no available vaccine. The mechanisms by which the virus overcomes host innate and adaptive immunity to persist in the majority of infected hepatocytes is currently unclear, in part due to our incomplete understanding of HCV-host interactions leading to immune disruption. We have previously demonstrated that chronic HCV infection leads to immunodysregulation mediated through up-regulation of negative immunomodulators, including programmed death-1 (PD-1), suppressor of cytokine signaling-1 (SOCS-1), and, most recently, T cell immunoglobulin and mucin domain protein-3 (Tim-3). While Tim-3 has been shown to play a critical role in T cell exhaustion during chronic viral infections, its expression and function o innate immune cells in HCV persistence and antiviral responses remain unknown. Natural killer (NK) cells comprise the first line of host defense against invading pathogens. Compromised NK cell functions have been reported in chronic HCV-infected individuals, but efforts to define the role of NK cells in clinical outcomes of HCV infection and treatment responses have focused primarily on traditional NK receptors, such as killer immunoglobulin-like receptors (KIRs). We have recently discovered that Tim-3 expression is up-regulated on NK cells isolated from HCV-infected individuals and on NK cells incubated with HCV-infected hepatocytes. Blockade of Tim-3 signaling restores HCV-mediated NK cell inhibition and apoptosis. Based on these novel findings, we hypothesize that HCV-induced Tim-3 expression on NK cells plays a pivotal role in immunodysregulation, such that blockade of Tim-3 signaling on NK cells will rescue impaired antiviral immune responses to HCV infection. To test this hypothesis, we will carry out the following specific aims: 1) Define the role of Tim-3 expression and its function on NK cells from HCV-infected patients who have received antiviral therapy with defined outcomes, compared with naturally resolved HCV infection or healthy subjects. 2) Determine the mechanisms by which Tim-3 is up-regulated on NK cells using an HCV-expressing hepatocyte model system, focusing on specific HCV antigen-mediated regulation of Tim-3 transcription, translation, biosynthesis and degradation. 3) Determine the effects of Tim-3 signaling in NK cells on host antiviral responses, including dendritic cell (DC) IL-12 expression, NK/natural T (NT) and CD4+/CD8+ T lymphocyte responses, as well as hepatocyte interferon (IFN) signaling and HCV replication. The overall goal of this proposal is to employ a translational approach to obtain a unified overview of how HCV-mediated Tim-3 up-regulation on NK cells alters host innate to adaptive immune responses to HCV infection, so as to develop effective strategies to combat this common viral disease.

Public Health Relevance

HCV is characterized by persistent infection and poor treatment response. Why this virus is able to persist in the majority of infected liver hepatocytes and more than half of the most prevalent HCV genotype-1 patients fail the standard antiviral treatment, remain unclear;disruption of both innate and adaptive immune responses, however, appears to play a major role. Based on our preliminary data, we suspect that a novel immunomodulator, Tim-3, is regulating the functions of innate immune cells, such as NK cells, leading to disruption of the transition from innate to adaptive immune responses during HCV infection. This project will examine whether and how Tim-3 expression is up-regulated on NK cells in individuals with chronic HCV infection following antiviral therapy, with a focus on the virus and host interactions in a novel system mimicking the HCV-infected liver as a model and manipulating Tim-3 signaling in NK cells as a tool. This study will facilitate effective approaches to improve antiviral therapy, and thus is significant and timely.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Academic Research Enhancement Awards (AREA) (R15)
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Special Emphasis Panel (ZRG1-IMM-K (90))
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Koshy, Rajen
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East Tennessee State University
Internal Medicine/Medicine
Schools of Medicine
Johnson City
United States
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