Presence of interferon-λ 4, male gender, absent/mild steatosis and low viral load augment antibody levels to hepatitis C virus

Jesper Waldenström,Kristoffer Hellstrand,Johan Westin,Staffan Nilsson,Peer Christensen,Martti Färkkilä,Kristine Mørch,Nina Langeland,Gunnar Norkrans,Martin Lagging

doi:10.1080/00365521.2021.1922750

Abstract

Objectives Despite recombinant interferon-λ 4 (IFN-λ4) demonstrating anti-viral activity in vitro and the ancestral functional gene (IFNL4) being conserved in all other primates, there has been speculation that IFN-λ4 may be detrimental in humans. In light of recent rekindled interest in humoral immunity, this study aimed at evaluating the impact of baseline characteristics, including IFNL4, on antibody levels to hepatitis C virus (HCV). Materials and methods Pretreatment sera from 279 well-characterized North European Caucasians with chronic HCV genotype 2 or 3 infection having undergone liver biopsy were analyzed regarding IFNL4 (rs12979860) and anti-HCV antibody levels using a commercially available assay. Results Patients producing IFN-λ4 had higher signal to cut-off (S/CO) anti-HCV antibody ratios as compared with those lacking IFN-λ4 (IFNL4 rs12979860 CT/TT versus CC, p<.0001, Mann–Whitney U-test). Additionally, in univariate analyses S/CO was significantly higher in men than women (p<.001), as well as in patients with absent/mild interface hepatitis (Ishak grade 0–2 versus 3–4, p = .009), and absent/mild steatosis (grade 0–1 versus 2–3, p = .0005). Also, an inverse correlation with HCV RNA level (rs = −0.14, p = .02) was noted. In multivariate analysis IFN-λ4, gender, steatosis and viral load remained independently associated. Conclusions To our knowledge, this is the first report that demonstrates that the ability to produce IFN-λ4, in addition to male gender, absent/mild steatosis, and lower viral load, augments antibody levels against HCV. This indicates that IFN-λ4 may be associated with T helper cell 2 (Th2) immune skewing, which might have clinical implications beyond HCV infection. ClinicalTrials.gov Identifier: NCT00143000

Highlights

Homozygous carriage of the C allele in rs12979860 in the proximity of the interleukin 28B gene (IL28B known as interferon-k 3 (IFNL3)) on chromosome 19 substantially increases the likelihood of spontaneous clearance of acute hepatitis C virus (HCV) infection [1] as well as improved outcome following interferon-based HCV therapy [2,3]
As IFNL4rs12979860 genotype is known to associate with interferon gamma-induced protein 10 (IP-10 aka CXCL10) [20], the correlation between IP-10 and signal to cut-off (S/CO) was explored, and a non-significant trend was noted towards higher anti-HCV antibody levels when IP-10 concentrations were lower (p 1⁄4 .06)
The main findings of this study were that ability to produce interferon-k 4 (IFN-k4), in addition to male gender, absent/mild steatosis, and lower viral load, augmented antibody responses against HCV, and that highest antibody ratios were observed in carriers with two functional genes (IFNL4rs12979860 TT homozygotes) in both genders

Summary

Introduction

Homozygous carriage of the C allele in rs12979860 in the proximity of the interleukin 28B gene (IL28B known as interferon-k 3 (IFNL3)) on chromosome 19 substantially increases the likelihood of spontaneous clearance of acute hepatitis C virus (HCV) infection [1] as well as improved outcome following interferon-based HCV therapy [2,3]. Recombinant IFN-k4 signals through the IFN-k receptor 1 [6] to activate the JAK/STAT pathway, which subsequently induces expression of interferon-stimulated genes (ISGs). This in turn leads to high anti-viral activity, the amino acid substitution K154 fixed throughout evolution

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Conclusion