Immunological dynamics associated with rapid virological response during the early phase of type I interferon therapy in patients with chronic hepatitis C.

Jae-Won Lee,Hyun Mu Shin,Won-Woo Lee,Yuri Kim,Ji-Yeob Choi,Dong-Hyun Kim,Won Kim,Byeong Gwan Kim,Nam-Hyuk Cho,Myung-Sik Choi,Eun-Kyung Kwon,Chan-Ki Min,Eui-Cheol Shin

doi:10.1371/journal.pone.0179094

Abstract

Type I interferons (IFNs) play an important role in antiviral immunity as well as immunopathogenesis of diverse chronic viral infections. However, the precise mechanisms regulating the multifaceted effects of type I IFNs on the immune system and pathological inflammation still remain unclear. In order to assess the immunological dynamics associated with rapid viral clearance in chronic hepatitis C patients during the acute phase of type I IFN therapy, we analyzed multiple parameters of virological and immunological responses in a cohort of 59 Korean hepatitis C patients who received pegylated IFN-α and ribavirin (IFN/RBV). Most of the Korean patients had favorable alleles in the IFN-λ loci for responsiveness to IFN/RBV (i.e., C/C in rs12979860, T/T in rs8099917, and TT/TT in rs368234815). Rapid virological response (RVR) was determined mainly by the hepatitis C virus genotype. Among the cytokines analyzed, higher plasma levels of IL-17A and FGF were observed in non-RVR patients infected with viral genotype 1 and IP-10 was consistently elevated in RVR group infected with genotype 2 during the early phase of antiviral therapy. In addition, these three cytokines were correlated each other, suggesting a functional linkage of the cytokines in antiviral responses during IFN/RBV therapy. A low baseline frequencies of regulatory T cells and γδ T cells, but high level of group 2 innate lymphoid cells, in peripheral bloods were also significantly associated with the RVR group, implicating a potential role of the cellular immunity during the early phase of IFN/RBV therapy. Therefore, the immunological programs established by chronic hepatitis C and rapid disruption of the delicate balance by exogenous type I IFN might be associated with the subsequent virological outcomes in chronic hepatitis C patients.

Highlights

Type I interferons (IFNs) play a significant role in antiviral immunity as well as immunopathogenesis of chronic inflammatory diseases
The Rapid virological response (RVR) group had significantly lower body mass index (BMI) (p = 0.006) and higher aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels (p = 0.026 in both parameters) prior to IFN-α and ribavirin (IFN/RBV) therapy compared to the non-RVR group
Thirty (83.3%) patients in the RVR group were infected with hepatitis C virus (HCV) genotype 2, while 19 (82.6%) patients in the non-RVR had genotype 1

Summary

Introduction

Type I interferons (IFNs) play a significant role in antiviral immunity as well as immunopathogenesis of chronic inflammatory diseases. An increasing amount of evidence shows that type I IFN responses can result in detrimental outcomes during viral infection by inducing immunosuppressive effects and triggering inflammation and tissue damage [1,2]. Chronic LCMV infection induces sustained expression of type I IFNs in dendritic cells, which in turn upregulate suppressive immune modulators such as IL-10 and PD-L1 in APCs [9,10]. A recent study reported that in vivo blockade of type I IFN signaling during chronic human immunodeficiency virus (HIV) infection diminished HIV-driven immune activation, decreased T cell exhaustion marker expression, restored HIV-specific CD8+ T cell function, and led to decreased viral replication [11]. The exact regulatory mechanism underlying the multifaceted effects of sustained type I IFN signaling on immunological mediators and pathological tissue damage during chronic viral infection remains elusive [12]

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Conclusion