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Hepatitis C virus impairs natural killer cell activity via viral serine protease NS3

 Chang Mo Yang  ;  Joo Chun Yoon  ;  Jeon Han Park  ;  Jae Myun Lee 
 PLOS ONE, Vol.12(4) : e0175793, 2017 
Journal Title
Issue Date
Carbamates/chemistry ; Carbamates/pharmacology ; Cell Line ; Cell Survival/drug effects ; Coculture Techniques ; Down-Regulation/drug effects ; Hepacivirus/enzymology* ; Hepatitis C/immunology ; Hepatitis C/pathology ; Hepatitis C/virology ; Humans ; Interferon-gamma/analysis ; Interferon-gamma/metabolism ; Interleukin-12/genetics ; Interleukin-12/metabolism ; Interleukin-12/pharmacology ; K562 Cells ; Killer Cells, Natural/drug effects ; Killer Cells, Natural/immunology* ; Killer Cells, Natural/metabolism ; Macrocyclic Compounds/chemistry ; Macrocyclic Compounds/pharmacology ; Microscopy, Confocal ; Natural Cytotoxicity Triggering Receptor 1/genetics ; Natural Cytotoxicity Triggering Receptor 1/metabolism ; Natural Cytotoxicity Triggering Receptor 3/genetics ; Natural Cytotoxicity Triggering Receptor 3/metabolism ; Quinolines/chemistry ; Quinolines/pharmacology ; Recombinant Proteins/biosynthesis ; Recombinant Proteins/isolation & purification ; Recombinant Proteins/pharmacology ; Serine Proteinase Inhibitors/chemistry ; Serine Proteinase Inhibitors/pharmacology ; Thiazoles/chemistry ; Thiazoles/pharmacology ; Viral Nonstructural Proteins/antagonists & inhibitors ; Viral Nonstructural Proteins/genetics ; Viral Nonstructural Proteins/metabolism*
Hepatitis C virus (HCV) infection is characterized by a high frequency of chronic cases owing to the impairment of innate and adaptive immune responses. The modulation of natural killer (NK) cell functions by HCV leads to an impaired innate immune response. However, the underling mechanisms and roles of HCV proteins in this immune evasion are controversial, especially in the early phase of HCV infection. To investigate the role of HCV nonstructural proteins especially NS3 in the impairment of NK functions, NK cells were isolated from the PBMCs by negative selection. To assess the direct cytotoxicity and IFN-γ production capability of NK cells, co-cultured with uninfected, HCV-infected, HCV-NS3 DNA-transfected Huh-7.5, or HCV-NS replicon cells. To determine the effect of an NS3 serine protease inhibitor, HCV-infected Huh-7.5 cells were treated with BILN-2061. Then, NK cells were harvested and further co-cultured with K-562 target cells. NK cell functions were analyzed by flow cytometry and enzyme-linked immunosorbent assay. When co-cultured with HCV-infected Huh-7.5 cells, the natural cytotoxicity and IFN-γ production capability of NK cells were significantly reduced. NK cell functions were inhibited to similar levels upon co-culture with HCV-NS replicon cells, NS3-transfected cells, and HCV-infected Huh-7.5 cells. These reductions were restored by BILN-2061-treatment. Furthermore, BILN-2061-treatment significantly increased degranulation against K-562 target cells and IFN-γ productivity in NK cells. Consistent with these findings, the expression levels of activating NK cell receptors, such as NKp46 and NKp30, were also increased. In HCV-infected cells, the serine protease NS3 may play a role in the abrogation of NK cell functions in the early phase of infection through downregulation of NKp46 and NKp30 receptors on NK cells. Together, these results suggest that NS3 represents a novel drug target for the treatment of HCV infections.
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1. College of Medicine (의과대학) > Dept. of Microbiology (미생물학교실) > 1. Journal Papers
Yonsei Authors
Park, Jeon Han(박전한) ORCID logo https://orcid.org/0000-0001-9604-3205
Lee, Jae Myun(이재면) ORCID logo https://orcid.org/0000-0002-5273-3113
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