Hepatitis C Virus (HCV) Eradication With Interferon-Free Direct-Acting Antiviral-Based Therapy Results in KLRG1+ HCV-Specific Memory Natural Killer Cells

Abstract

Direct acting antiviral therapies rapidly clear chronic hepatitis C virus (HCV) infection and restore natural killer (NK) cell function. We investigated NK cell memory formation following HCV clearance by examining NK cell phenotype and responses from control and chronic HCV patients before and after therapy following sustained virologic response at 12 weeks post-therapy (SVR12). NK cell phenotype at SVR12 differed significantly from paired pre-treatment samples, with an increase in maturation markers CD16, CD57 and KLRG1. HCV patients possessed stronger cytotoxic responses against HCV infected cells as compared to healthy controls; a response that further increased following SVR12. The antigen-specific response was mediated by KLRG1+ NK cells, as demonstrated by increased degranulation and proliferation in response to HCV antigen only. Our data suggest that KLRG1+ HCV-specific memory NK cells develop following viral infection, providing insight into their role in HCV clearance and relevance with regard to vaccine design.

Regulation of the human NK cell compartment by pathogens and vaccines

“…Consistent with these observations, a recent study of HCMV seropositive patients reported that high frequencies of adaptive CD57 + FcεR1γ − NK cells and elevated expression of PD‐1 were associated with high viral load in chronic HCV infection and were reduced after direct‐acting antiviral therapy (DAA) 57 . In a separate study, chronic HCV infection was similarly associated with higher frequencies of CD57 + and PD‐1 + NK cells compared to uninfected control individuals 58 . However, although PD1 expression frequency reduced after DAA, proportions of CD57 + and KLRG1 + cells increased after treatment, suggesting ongoing expansion of highly differentiated NK cells 58 .…”

“…58 The slightly different NK cell outcomes in these two studies may be explained by differences in HCMV status, HCV viral genotype, viral load and treatment regimen. 57,58…”

“…57 In a separate study, chronic HCV infection was similarly associated with higher frequencies of CD57 + and PD-1 + NK cells compared to uninfected control individuals. 58 However, although PD1 expression frequency reduced after DAA, proportions of CD57 + and KLRG1 + cells increased after treatment, suggesting ongoing expansion of highly differentiated NK cells. 58 The slightly different NK cell outcomes in these two studies may be explained by differences in HCMV status, HCV viral genotype, viral load and treatment regimen.…”

“…58 However, although PD1 expression frequency reduced after DAA, proportions of CD57 + and KLRG1 + cells increased after treatment, suggesting ongoing expansion of highly differentiated NK cells. 58 The slightly different NK cell outcomes in these two studies may be explained by differences in HCMV status, HCV viral genotype, viral load and treatment regimen. 57,58…”

Immunological Mechanisms for Hepatocellular Carcinoma Risk after Direct-Acting Antiviral Treatment of Hepatitis C Virus Infection

“…These agents also have a favorable side effect profile, and their administration periods are shorter than those of their traditional counterparts. Despite a nearly 100% cure rate, DAA therapy does not prevent HCV reinfection [ 4 ].…”