P35-17. Nonreversible imprint on the soluble and cellular immune system by chronic hepatitis C

Julia Hengst [1,2], Benedikt Strunz [2], Verena Schlaphoff [1], Katja Deterding [1], Christine S. Falk [3], Michael P. Manns [1], Hans-Gustaf Ljunggren [2], Edwin Leeansyah [2], Markus Cornberg [1], Johan Sandberg [2], Heiner Wedemeyer [1], and Niklas K. Björkström [2]
Affiliates: [1] Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany. [2] Center for Infectious Medicine, Department of Medicine, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden. [3] Institute of Transplant Immunology, IFB-Tx, Hannover Medical School, Hannover, Germany.

Background
Persistent infection with the hepatitis C virus (HCV) is accompanied by an inflammation of liver tissue and profound alterations in the cytokine milieu and in immune cell subset distribution in peripheral blood. In particular, the chronic infection can cause immune exhaustion. Mucosal-associated invariant T (MAIT) cells are innate-like, unconventional effector T cells that are evolutionary conserved. It has been previously shown that these cells are reduced in frequency in chronic hepatitis C virus (cHCV) infection. Novel treatment regiments with direct-acting antivirals (DAAs) targeting HCV offer the unique opportunity to study how viral clearance affects the cytokine milieu, the immune cell subset composition as well as the phenotype and functional capacity of immune cells.

Methods
Multianalyte profiling of 50 cytokines and chemokines in the plasma of patients with cHCV infection was performed. Additionally, multi-color flow cytometry was applied to analyze the phenotype and functionality of MAIT cells. Twenty-six patients with cHCV infection, treated with sofosbuvir and ribavirin for 24 weeks, were sampled before, during and after therapy. Healthy donors and nonalcoholic steatohepatitis patients were included as controls.

Results
The cytokine milieu was markedly altered in cHCV patients as compared to healthy controls and NASH patients. Moreover, SVR and relapse patients could be distinguished apart by baseline levels of several cytokines and chemokines and the expression levels of distinct cytokines were affected by the severity of liver disease. During successful DAA therapy, significant changes of the cytokine milieu were observed, however the pattern was not normalized for the majority of parameters. Additionally, out of all major immune cell types in human peripheral blood, MAIT cells were the most dramatically reduced cells in cHCV infection. Remaining MAIT cells exhibited an activated and exhausted phenotype with an altered transcription factor expression profile. Moreover, MAIT cell function was defective and these alterations did not restore upon successful treatment and clearance of HCV.

Conclusions
The results show that cHCV infection appears to disrupt the cytokine milieu and cause phenotypic alteration and dysfunction of MAIT cells. These alterations persist even after viral clearance. Thus, in contrast to NK cells (Serti E, et al., 2015, Gastroenterology) and antigen-specific CD8+ T cells (Martin B, et al., 2014, J Hepatol), which were indicated to normalize upon successful DAA treatment, MAIT cells were not restored after successful HCV clearance using DAA therapy. In conclusion, the results demonstrate that HCV cure does not lead to reinvigoration of all parts of the soluble and cellular immune system.