Background and Aims: Patients with chronic hepatitis C virus (HCV) infection display great variability in disease activity and progression. While virus-specific adaptive immune responses have been extensively characterized and found to be impaired in chronic hepatitis C, the role of innate immune responses in disease activity and progression of chronic hepatitis C is not well understood.
Background & Aims
Mathematical modeling of hepatitis C virus (HCV) kinetics indicated that the cellular immune response contribute to interferon (IFN)-induced clearance of HCV. We investigated a potential role of natural killer (NK) cells in this process.
Methods
Phenotype and function of blood and liver NK cells were studied during the first 12 weeks of treatment with pegylated IFN-alfa and ribavirin, the time period used to define the early virological response.
Results
Within hours of treatment initiation, NK cells of patients that had an early virological response increased expression of the activating receptors NKG2D, NKp30, and CD16; they decreased expression of NKG2C and 2B4, along with the inhibitory receptors SIGLEC7 and NKG2A, resulting in NK cell activation. NK cell cytotoxicity, measured by degranulation and TRAIL production, peaked after 24 h (P<.01), concomitant with an increase in alanine aminotransferase levels (P<.05), whereas IFN-g production decreased within 6 h and did not recover for more than 4 weeks (P<.05). NK cells from liver biopsies taken 6 h after treatment initiation had increased numbers of cytotoxic CD16+ NK cells (P<.05) and a trend towards increased production of TRAIL. Degranulation of peripheral blood NK cells correlated with the treatment-induced, first phase decreases in viral load (P<.05) and remained higher in early virological responders than in nonresponders for weeks.
Conclusions
IFN activates NK cells early after treatment is initiated. Their cytotoxic function, in particular, is strongly induced, which correlates to the virologic response. Therefore, NK cell activation indicates responsiveness to IFN-g–based treatment and indicates the involvement of the innate immune cells in viral clearance.
Natural killer (NK) cells exhibit a polarized phenotype with increased cytotoxicity and decreased IFN- γ production in chronic hepatitis C virus (HCV) infection. Here we asked whether this is due to type I interferon (IFN)-induced expression and phosphorylation levels of signal transducer and activator of transcription (STAT) molecules in NK cells and whether it affects the response and refractoriness of NK cells to IFN-α-based therapy of hepatitis C. STAT1 levels in NK cells were significantly higher in patients with chronic HCV infection than in uninfected controls. STAT1 levels and induction of phosphorylated STAT1 (pSTAT1) increased further during IFN-α-based therapy with preferential STAT1 over STAT4 phosphorylation. Induction of pSTAT1 correlated with increased NK cytotoxicity (TRAIL expression and degranulation) and decreased IFN-γ production. NK cells from patients with a greater than 2 log10 first phase HCV RNA decline to IFN-α-based therapy (>99% IFN effectiveness) displayed strong pSTAT1 induction in vivo and were refractory to further stimulation in vitro. In contrast, NK cells from patients with a less than 2 log10 first phase HCV RNA decline exhibited lower pSTAT1 induction in vivo (p=0.024) but retained greater IFN-α responsiveness in vitro (p=0.024). NK cells of all patients became refractory to in vivo and in vitro stimulation by IFN-α during the second phase virological response.
Conclusion
These data show that IFN-α-induced modulation of STAT1/4 phosphorylation underlies the polarization of NK cells towards increased cytotoxicity and decreased IFN-γ production in HCV infection, and that NK cell responsiveness and refractoriness correlate to the antiviral effectiveness of IFN-α-based therapy.
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