Journal
JOURNAL OF INFECTIOUS DISEASES
Volume 209, Issue 10, Pages 1591-1601Publisher
OXFORD UNIV PRESS INC
DOI: 10.1093/infdis/jit677
Keywords
hepatitis C; liver; natural killer; human; infection
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Funding
- National, and Department of Veterans Affairs Institute of Allergy and Infectious Diseases, National Institutes of Health [R01 DK068361, R21 AI100809-01, VA Merit 110BX001894-01, R01 AI069195]
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Background. Natural killer (NK) cells are implicated in the pathogenesis of hepatitis C virus (HCV) infection and outcome of interferon (IFN)-alpha based therapy, although mechanisms remain unclear. Methods. To evaluate NK ability to control HCV infection, we analyzed healthy donor and HCV-infected donor NK-cell cytolytic activity directed at HCV-infected target cells. Results. HCV-infected subjects' natural cytotoxicity receptor (NCR)-dependent NK-cell cytolytic activity directed at HCV-infected and uninfected Huh7.5 target cells was greater than that of cells from healthy donors, and this localized to the African American subset. However, IFN-alpha-enhanced NK cytolytic function was lower in HCV-infected subjects, again localized mainly to the African American subset. Additionally, whereas HCV-infected Huh7.5 cells were more readily targeted than uninfected cells, the selectivity of cytolytic activity for infected targets was lower during HCV infection and after IFN-alpha stimulation, and lower selectivity was in part attributable to greater NKp46 expression. Furthermore, cytolytic activity was associated with higher serum aspartate aminotransferase, rs12979860 IL28B genotype, and in vivo response to pegylated IFN/ribavirin therapy. Conclusions. These data indicate that during chronic HCV infection, race-associated increase in NCR expression and IL28B-associated cytolytic activity may participate in host response to IFN-a-containing HCV therapy.
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