Partial restoration of immune response in Hepatitis C patients after viral clearance by direct-acting antiviral therapy

• Published in: PloS one 2021-07, Vol.16 (7), p.e0254243
• Main Authors: Llorens-Revull, Meritxell, Costafreda, Maria Isabel, Rico, Angie, Guerrero-Murillo, Mercedes, Soria, Maria Eugenia, Píriz-Ruzo, Sofía, Vargas-Accarino, Elena, Gabriel-Medina, Pablo, Rodríguez-Frías, Francisco, Riveiro-Barciela, Mar, Perales, Celia, Quer, Josep, Sauleda, Silvia, Esteban, Juan Ignacio, Bes, Marta
• Format: Article
• Language: English
• Subjects: Adult; Aged; Antiviral agents; Antiviral Agents - therapeutic use; Antiviral drugs; Biochemistry; Biology and Life Sciences; Care and treatment; CD223 antigen; CD4 antigen; CD4-Positive T-Lymphocytes - immunology; CD8 antigen; CD8-Positive T-Lymphocytes - immunology; Cell proliferation; Cell surface; Chronic infection; Cytokines; Dosage and administration; Enzyme-linked immunosorbent assay; Evaluation; Female; Flow cytometry; Funding; Genetic aspects; Genotype & phenotype; Hepacivirus - drug effects; Hepacivirus - immunology; Hepatitis; Hepatitis C; Hepatitis C, Chronic - drug therapy; Hepatitis C, Chronic - immunology; Hepatitis C, Chronic - virology; Hospitals; Humans; Immune clearance; Immune response; Immune system; Infections; Interferon; Interferon-gamma - immunology; Interferon-gamma - metabolism; Interleukin 2; Internal medicine; Laboratories; Liver diseases; Lymphocytes; Lymphocytes T; Male; Medicine and Health Sciences; Middle Aged; Patients; PD-1 protein; Phenotypes; Programmed Cell Death 1 Receptor - immunology; Programmed Cell Death 1 Receptor - metabolism; Restoration; Reversion
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0254243

HCV CD4+ and CD8+ specific T cells responses are functionally impaired during chronic hepatitis C infection. DAAs therapies eradicate HCV infection in more than 95% of treated patients. However, the impact of HCV elimination on immune responses remain controversial. Here, we aimed to investigate whether HCV cure by DAAs could reverse the impaired immune response to HCV. We analyzed 27 chronic HCV infected patients undergoing DAA treatment in tertiary care hospital, and we determined the phenotypical and functional changes in both HCV CD8+ and CD4+ specific T-cells before and after viral clearance. PD-1, TIM-3 and LAG-3 cell-surface expression was assessed by flow cytometry to determine CD4+ T cell exhaustion. Functional responses to HCV were analyzed by IFN-Ɣ ELISPOT, intracellular cytokine staining (IL-2 and IFN-Ɣ) and CFSE-based proliferation assays. We observed a significant decrease in the expression of PD-1 in CD4+ T-cells after 12 weeks of viral clearance in non-cirrhotic patients (p = 0.033) and in treatment-naive patients (p = 0.010), indicating a partial CD4 phenotype restoration. IFN-Ɣ and IL-2 cytokines production by HCV-specific CD4+ and CD8+ T cells remained impaired upon HCV eradication. Finally, a significant increase of the proliferation capacity of both HCV CD4+ and CD8+ specific T-cells was observed after HCV elimination by DAAs therapies. Our results show that in chronically infected patients HCV elimination by DAA treatment lead to partial reversion of CD4+ T cell exhaustion. Moreover, proliferative capacity of HCV-specific CD4+ and CD8+ T cells is recovered after DAA's therapies.