A hepatitis C virus-encoded, nonstructural protein (NS3) triggers dysfunction and apoptosis in lymphocytes: role of NADPH oxidase-derived oxygen radicals

J Leukoc Biol. 2004 Dec;76(6):1180-6. doi: 10.1189/jlb.0704387. Epub 2004 Sep 15.


The persistent infection caused by hepatitis C virus (HCV) is presumably explained by a deficient immune response to the infection, but the basis for the inefficiency of immune-mediated virus eradication is not known in detail. This study addresses mechanisms of relevance to dysfunction of cytotoxic lymphocytes in HCV infection, with a focus on the role of phagocyte-derived oxygen radicals. We show that NS3, a nonstructural, HCV-encoded protein, induces a prolonged release of oxygen radicals from mononuclear and polymorphnuclear phagocytes by activating a key enzyme in radical formation, the reduced nicotinamide adenine dinucleotide phosphate (NADPH) oxidase. The NS3-activated phagocytes, in turn, induced dysfunction and/or apoptosis in three major subsets of lymphocytes of relevance to defense against HCV infection: CD3+/56- T cells, CD3-/56+ natural killer (NK) cells, and CD3+/56+ NKT cells. Two inhibitors of the NADPH oxidase, histamine and diphenylene iodonium, suppressed the NS3-induced oxygen radical production and efficiently protected lymphocytes against NS3-induced apoptosis and dysfunction. In conclusion, we propose that NS3, by triggering oxygen radical formation in phagocytes, may contribute to the dysfunction of antiviral lymphocytes in HCV-infected liver tissue and that strategies to circumvent oxidative stress may be useful in preventing HCV-associated carcinogenesis and facilitating lymphocyte-mediated clearance of infected cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis / immunology*
  • Cell Communication / immunology
  • Cell Separation
  • Cytotoxicity Tests, Immunologic
  • Enzyme Inhibitors / pharmacology
  • Hepacivirus / immunology
  • Hepacivirus / metabolism*
  • Humans
  • Immune Tolerance / immunology
  • Killer Cells, Natural / drug effects
  • Killer Cells, Natural / immunology
  • Killer Cells, Natural / metabolism
  • Lymphocytes / drug effects*
  • Lymphocytes / immunology
  • Lymphocytes / metabolism
  • NADPH Oxidases / antagonists & inhibitors
  • NADPH Oxidases / metabolism*
  • Oxidative Stress / immunology
  • Phagocytes / metabolism
  • Reactive Oxygen Species / metabolism*
  • T-Lymphocytes / drug effects
  • T-Lymphocytes / immunology
  • T-Lymphocytes / metabolism
  • Viral Nonstructural Proteins / pharmacology*


  • Enzyme Inhibitors
  • NS3 protein, hepatitis C virus
  • Reactive Oxygen Species
  • Viral Nonstructural Proteins
  • NADPH Oxidases