Chronic genotype 1 hepatitis C along with cirrhosis drives a persistent imprint in virus‐specific CD8+ T cells after direct‐acting antiviral therapies

Chronic hepatitis C virus (HCV) infection impairs HCV CD8+ T‐cell responses, while it could influence immune responses towards unrelated viruses/vaccines (e.g. cytomegalovirus, CMV, and influenza, Flu). The aim of our study was to delineate whether restoration of these virus‐specific CD8+ T cells occurs after direct‐acting antiviral (DAA) therapies and particularly in patients with cirrhosis. We performed longitudinal analysis (baseline, week 4, follow‐up [FU] 12 and FU48) of virus‐specific CD8+ T cells by multicolour flow cytometry in HCV‐cirrhotic patients undergoing DAA therapy (n = 26) after in vitro expansion with immunodominant HCV, CMV and Flu epitopes restricted by HLA‐A*02. HCV noncirrhotic patients (n = 9) and healthy individuals (n = 10) served as controls. We found that the proliferative capacity of HCV‐specific CD8+ T cells increased from baseline up to FU48 in a significant proportion of cirrhotic and noncirrhotic patients. Nevertheless, these cells remained poor cytokine producers in both patient groups, regardless of the down‐regulation of inhibitory co‐regulatory receptors in HCV‐cirrhotic patients at FU48. Likewise, high expression levels of these exhaustion markers were detected in CMV‐/Flu‐specific CD8+ T cells in HCV‐cirrhotic patients at all time points, albeit without affecting their proliferative capacity or cytokine production. We conclude that DAA therapies induce restoration of the proliferative capacity of HCV‐specific CD8+ T cells. However, these cells remain phenotypically and functionally impaired. Contrarily, the ‘exhausted’ phenotype in CMV‐/Flu‐specific CD8+ T cells in HCV‐cirrhotic patients did not associate with their functions. Larger studier with longer follow‐up may elucidate whether this complex interplay influences the outcome of cirrhotic patients.