Ribavirin improves the IFN-γ response of natural killer cells to IFN-based therapy of hepatitis C virus infection.
Ribavirin (RBV) is an important component of interferon (IFN)-based and direct antiviral treatment regimens for hepatitis C virus (HCV) infection. Immunomodulation, in particular improvement of the host IFN response, has been proposed as RBV's mechanism of action. Natural killer (NK) cells are sensitive biomarkers for IFN-α/β receptor signaling, as NK cell cytotoxicity and IFN-γ production are regulated by signal transducer and activator of transcription (STAT)1- and STAT4-phosphorylation, respectively. Specifically, pSTAT1-dependent NK cell cytotoxicity increases and pSTAT4-dependent IFN-γ production decreases in response to endogenous, virus-induced IFN-α and during IFN-α-based therapy. To assess whether RBV has a direct effect on NK cells and/or improves the IFN-γ response of NK cells in the presence of IFN-α, we prospectively studied 22 HCV patients with and 32 patients without 4 weeks of RBV pretreatment, who all received subsequent pegylated (Peg)IFN/ribavirin combination therapy. During RBV pretreatment, both the frequency of CD56(dim) NK cells with cytotoxic effector functions and the frequency of CD56(bright) NK cells with the capacity to produce IFN-γ decreased (P = 0.049 and P = 0.001, respectively). In vitro or in vivo exposure of NK cells to RBV improved the pSTAT4 (P < 0.01) but not pSTAT1 response of NK cells to subsequent stimulation with IFN-α. This was associated with an increase in IFN-γ production but not cytotoxicity of NK cells during subsequent IFN-α-based therapy. The frequency of IFN-γ-producing NK cells was greater in fast second-phase virological responders than in slow responders.


CONCLUSIONS
RBV enhances the pSTAT4 and IFN-γ response of NK cells to IFN-α-stimulation.
Immunology Section, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, DHHS, Bethesda, MD; Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, DHHS, Bethesda, MD.
Jens M
JM
Werner
Elisavet
E
Serti
Xenia
X
Chepa-Lotrea
Jonathan
J
Stoltzfus
Golo
G
Ahlenstiel
Mazen
M
Noureddin
Jordan J
JJ
Feld
T Jake
TJ
Liang
Yaron
Y
Rotman
Barbara
B
Rehermann
D000328:Adult; D000998:Antiviral Agents / Q000494:pharmacology / Q000627:therapeutic use*; D004359:Drug Therapy, Combination; D005260:Female; D016174:Hepacivirus; D006526:Hepatitis C / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D066298:In Vitro Techniques; D016898:Interferon-alpha / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use*; D007371:Interferon-gamma / Q000378:metabolism*; D007694:Killer Cells, Natural / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D011092:Polyethylene Glycols / Q000494:pharmacology / Q000627:therapeutic use*; D011446:Prospective Studies; D011994:Recombinant Proteins / Q000494:pharmacology / Q000627:therapeutic use; D012254:Ribavirin / Q000494:pharmacology / Q000627:therapeutic use*; D050794:STAT1 Transcription Factor / Q000378:metabolism; D050797:STAT4 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D016896:Treatment Outcome
D000998:Antiviral Agents; D016898:Interferon-alpha; D011994:Recombinant Proteins; D050794:STAT1 Transcription Factor; D050797:STAT4 Transcription Factor; D011092:Polyethylene Glycols; D012254:Ribavirin; D007371:Interferon-gamma; C100416:peginterferon alfa-2a