IFN‐λ3 polymorphism indirectly influences NK cell phenotype and function during acute HCV infection

Abstract

IntroductionPolymorphisms in the type III interferon IFN‐λ3 and the killer cell immunoglobulin‐like receptor (KIR) genes controlling the activity of natural killer (NK) cells can predict spontaneous resolution of acute hepatitis C virus (HCV) infection. We hypothesized that IFN‐λ3 polymorphism may modulate NK cell function during acute HCV.MethodsWe monitored the plasma levels of type III IFNs in relation to the phenotype and the function of NK cells in a cohort of people who inject drugs (PWID) during acute HCV infection with different outcomes.ResultsEarly acute HCV was associated with high variability in type III IFNs plasma levels and the favorable IFN‐λ3 CC genotype was associated with higher viral loads. Reduced expression of Natural Killer Group Protein 2A (NKG2A) was associated with lower IFN‐λ3 plasma levels and the CC genotype. IFN‐γ production by NK cells was higher in individuals with the CC genotype during acute infection but this did not prevent viral persistence. IFN‐λ3 plasma levels did not correlate with function of NK cells and IFN‐λ3 prestimulation did not affect NK cell activation and function.ConclusionsThese results suggest that IFN‐λ3 polymorphism indirectly influences NK cell phenotype and function during acute HCV but other factors may act in concert to determine the outcome of the infection.

Interleukin-28B Polymorphism is a Pharmacogenetic Predictor during Sofosbuvir Plus Pegylated Interferon and Ribavirin Therapy for Chronic Hepatitis C Egyptian Patients

“…Currently, there is a strong association between the rate of spontaneous clearance of HCV and IFN-λ polymorphisms [24]. Furthermore, killer cell immunoglobulin-like receptor (KIR) genes with IFN-λ3 polymorphisms indirectly influence the activity of natural killer (NK) cells and can predict spontaneous resolution of acute HCV infection [25].…”

Type III Interferons in Hepatitis C Virus Infection

“…One report also found no difference in serum levels of IFN-λ between HCV treatment responders and non-responders (30). Our group has demonstrated that serum levels of IFN-λ3 were highly variable, but were lower in individuals bearing the favorable IFN-λ3 CC allele (31). Altogether, type III IFN genotyping has been, so far, a more accurate predictor for HCV infection or treatment outcome compared to the circulating levels of the cytokines.…”

“…However, these data were difficult to reproduce in other cohorts. The IFN-λ3 rs12979860 CC genotype was associated with decreased levels of the inhibitory receptor NKG2A after infection resolution (31). Individuals bearing the CC genotype also displayed increased NK cell function measured by IFN-γ production after stimulation irrespective of infectious outcome suggesting that IFN-λ genotype influenced NK cell function but that this was not sufficient to achieve spontaneous HCV clearance (31).…”

“…The IFN-λ3 rs12979860 CC genotype was associated with decreased levels of the inhibitory receptor NKG2A after infection resolution (31). Individuals bearing the CC genotype also displayed increased NK cell function measured by IFN-γ production after stimulation irrespective of infectious outcome suggesting that IFN-λ genotype influenced NK cell function but that this was not sufficient to achieve spontaneous HCV clearance (31). Although IFNLR1 mRNA expression could be detected in NK cells (59, 60), they express very low levels of the specific type III IFN receptor (IFN-λR1) on cell surface, even after IFN-α stimulation (31, 61, 62).…”

“…Individuals bearing the CC genotype also displayed increased NK cell function measured by IFN-γ production after stimulation irrespective of infectious outcome suggesting that IFN-λ genotype influenced NK cell function but that this was not sufficient to achieve spontaneous HCV clearance (31). Although IFNLR1 mRNA expression could be detected in NK cells (59, 60), they express very low levels of the specific type III IFN receptor (IFN-λR1) on cell surface, even after IFN-α stimulation (31, 61, 62). Treatment of purified NK cells with IFN-λ had no effect on neither NK cytotoxicity nor cytokine production (31, 60, 62, 63).…”