The Clinical Features of Patients with Chronic Hepatitis C Virus Infections Are Associated with Killer Cell Immunoglobulin-Like Receptor Genes and Their Expression on the Surface of Natural Killer Cells.

Ariel Podhorzer,Melisa Dirchwolf,Santiago Belen,Hugo Fainboim,Leonardo Fainboim,Andrés Machicote,Silvia Paz,Luis G Podestá,Silvina Montal

doi:10.3389/fimmu.2017.01912

Abstract

Killer cell immunoglobulin-like receptor (KIR) genes are known to play a role in the acute phase of hepatitis C virus (HCV) infection. The present study investigated their roles in chronic HCV (CHCV) infection by analyzing the phenotypes and function of natural killer (NK) and T cells that express KIRs. T cells from CHCV patients showed a more differentiated phenotype, and NK cells exhibited an activated profile. These observations are consistent with the increased expression of the degranulation marker CD107a observed after PMA stimulation. We explored the correlations between the expression of KIR genes and lectin type-C receptors with clinical factors that predict progression to fibrosis and cirrhosis. The expression levels of KIR2DS3 and the functional alleles of KIR2DS4-FL were increased in patients with intermediate and high viral loads. Homozygous KIR2DS4 was also associated with the presence of cirrhosis. In the group of individuals with a shorter infection time who developed cirrhosis, we detected decreased expression of KIR3DL1 in CD56dim NK cells in the presence of its ligand. Similarly, in the group of patients with late CHCV infections complicated with cirrhosis, we detected lower expression of the strong inhibitory receptor NKG2A in CD56bright NK cells. We also detected an increase in NKG2C expression in CD56dim NK cells in CHCV patients who displayed high necroinflammatory activity. Decreased KIR3DL2 expression in CD56dim and CD56bright NK cells was associated with a high body mass index, and KIR3DL2 expression may be one factor associated with the more rapid progression of CHCV to fibrosis in patients.

Highlights

Hepatitis C virus infects over 170 million people worldwide [1]
According to early genetic studies, spontaneous hepatitis C virus (HCV) clearance is observed in patients with the KIR2DL3/HLA-C1 compound genotype, which results in a lower activation threshold for natural killer (NK) cells [4]
We examined the role of NK and T cells in chronic HCV (CHCV) patients and analyzed the killer cell immunoglobulin-like receptors (KIR) genotype and their protein levels on the surface of peripheral blood and liver cells

Summary

Introduction

Hepatitis C virus infects over 170 million people worldwide [1]. During the acute phase, a small proportion of individuals can naturally clear HCV using NK cells. Based on studies of health-care workers exposed to small amounts of HCV, activated NK cells may participate in controlling acute infection and subsequent HCV-specific T-cell response [2]. The innate immune response to an infection is likely to influence the type of adaptive immune response that develops and will determine whether the virus is cleared or develops into a chronic infection [reviewed in Rehermann [5]]. NK cells are divided into functionally distinct subsets based on their level of CD56 surface expression: the mainly cytotoxic CD56dim population and the more immunoregulatory cytokine-producing CD56bright NK cell subset. The functions of both NK cell subsets are modulated by inhibitory and activating signals provided by distinct classes of receptors. The role of KIR genes in the chronic stage of infection has been mostly identified at the genomic level [11, 12] or has been associated with the role of HCV in the development of HCV-associated diseases [13, 14]

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