In Chronic Hepatitis C Infection, Myeloid-Derived Suppressor Cell Accumulation and T Cell Dysfunctions Revert Partially and Late After Successful Direct-Acting Antiviral Treatment.

Valentina Telatin,Eleonora Castelli,Francesco Nicoli,Chiara Frasson,Antonella Caputo,Elke Erne,Francesco Barbaro,Nicola Menegotto,Giorgio Palù

doi:10.3389/fcimb.2019.00190

Abstract

Chronic HCV infection is characterized by several immunological alterations, such as the accumulation of suppressor cells and of hyperactivated T lymphocytes. However, it is unclear whether direct-acting antiviral (DAA)-mediated HCV clearance restores immune dysfunctions. We performed a phenotypic characterization by flow cytometry of different immune cell subsets, including monocytic myeloid-derived suppressor cells (M-MDSCs) and T lymphocytes in 168 patients with persistent HCV infection not treated, under DAA therapies and sustained virological responders. Chronic HCV infection prompted the accumulation of M-MDSCs independently of patient and clinical characteristics, and altered their metabolic properties. HCV RNA was undetectable in the majority of patients just after few weeks of DAA therapy, whereas M-MDSC levels normalized only 6 months after therapy. In addition, HCV infection deeply perturbed the T cell compartment since a re-distribution of memory CD4+ and CD8+ T cells was observed at the expenses of naïve cells, and memory T lymphocytes displayed increased activation. Notably, these features were only partially restored by DAA therapies in the CD4, but not in the CD8, compartment as high immune activation levels persisted in the terminally differentiated memory CD8+ T cells even more than 1 year after sustained virological response. Together, these results suggest that successful DAA therapies do not lead to full immunological reconstitution as fast as viral clearance.

Highlights

The World Health Organization (WHO) estimates that more than 70 million people are chronically infected with hepatitis C virus (HCV), causing about 400,000 deaths every year, and that ∼3–4 million new infections occur each year worldwide (WHO, 2018)
Few studies suggested that HCV promotes the increase of myeloid-derived suppressor cells (MDSCs) (Tacke et al, 2012; Cai et al, 2013; Ning et al, 2015; Pang et al, 2016)
We observed their accumulation in individuals with chronic HCV infection

Summary

Introduction

The World Health Organization (WHO) estimates that more than 70 million people are chronically infected with hepatitis C virus (HCV), causing about 400,000 deaths every year, and that ∼3–4 million new infections occur each year worldwide (WHO, 2018). The low access to this new generation of drugs in low income countries, the detection in few patients of occult HCV infection (Attar and Van Thiel, 2015; Elmasry et al, 2017) and the emergence of drug resistance and suboptimal activity toward some genotypes (Sun et al, 2018; Tavares et al, 2018) occasionally reported in DAA-treated subjects could threaten the achievement of HCV eradication in the absence of an effective vaccine Several alterations of both innate and adaptive immunity occur in chronically HCV-infected patients (Fernandez-Ponce et al, 2017), including increased level of myeloid-derived suppressor cells (MDSCs), that may inhibit T cell responses favoring viral escape and disease progression (Ning et al, 2015). Little is known about the role of DAA therapies on the restoration of MDSC numbers

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