Restoration of HCV-specific T cell functions by PD-1/PD-L1 blockade in HCV infection: Effect of viremia levels and antiviral treatment

• Published in: Journal of hepatology 2008-04, Vol.48 (4), p.548-558
• Main Authors: Urbani, Simona, Amadei, Barbara, Tola, Daniela, Pedrazzi, Giuseppe, Sacchelli, Luca, Cavallo, Maria Cristina, Orlandini, Alessandra, Missale, Gabriele, Ferrari, Carlo
• Format: Article
• Language: English
• Subjects: Antibiotics. Antiinfectious agents. Antiparasitic agents; Antigens, CD - drug effects; Antigens, CD - metabolism; Antiviral agents; Antiviral Agents - therapeutic use; Apoptosis Regulatory Proteins - antagonists & inhibitors; Apoptosis Regulatory Proteins - metabolism; B7-H1 Antigen; Biological and medical sciences; CD4+ T cells; CD8+ T cells; Cell Proliferation - drug effects; Dendritic Cells - drug effects; Dendritic Cells - immunology; Dendritic Cells - pathology; Flow Cytometry; Follow-Up Studies; Gastroenterology and Hepatology; Gastroenterology. Liver. Pancreas. Abdomen; Hepacivirus - drug effects; Hepacivirus - genetics; Hepacivirus - immunology; Hepatitis C Antibodies - analysis; Hepatitis C Antibodies - immunology; Hepatitis C virus; Hepatitis C, Chronic - drug therapy; Hepatitis C, Chronic - immunology; Hepatitis C, Chronic - virology; Human viral diseases; Humans; IFN α/ribavirin therapy; Infectious diseases; Interferon-gamma - therapeutic use; Medical sciences; PD-1; PD-L1; Pharmacology. Drug treatments; Programmed Cell Death 1 Receptor; RNA, Viral - drug effects; RNA, Viral - genetics; T cell failures; T-Lymphocytes - drug effects; T-Lymphocytes - immunology; T-Lymphocytes - pathology; Time Factors; Treatment Outcome; Viral diseases; Viral hepatitis; Viremia - drug therapy; Viremia - immunology; Viremia - virology
• ISSN: 0168-8278; 1600-0641
• DOI: 10.1016/j.jhep.2007.12.014

Background/Aims HCV-specific T cells in acute hepatitis C with subsequent chronic evolution are dysfunctional and most of them express PD-1. The aim of the study was to investigate to what extent the antiviral T cell function can be restored by reversing T cell exhaustion by PD-1/PD-L1 blockade and to assess whether this restoration is favored by IFN-α treatment. Methods PD-1 and PD-L1 expression was studied on T cells and dendritic cells, respectively, of 14 patients with acute hepatitis C and different evolutions of infection. The effect of anti-PD-L1 was analyzed on proliferation, cytokine production and cytolytic activity of CD4 and CD8 T cells. Results While PD-1 expression dropped concurrently with spontaneous or IFN-α induced HCV–RNA decline, PD-L1 levels on dendritic cells increased during IFN-α treatment. Anti-PD-L1 antibodies improved expansion and cytokine production but not the cytolytic activity of HCV-specific T cells. This restoration tended to be greater at lower levels of viremia and PD-1 expression and during PEG-IFNα treatment. Conclusions PD-1/PD-L1 blockade has an immunoregulatory activity which may synergize with the antiviral effect of IFN-α therapy and should be thus explored further in long-lasting chronic HCV infections in the perspective of improving the efficacy of available antiviral treatments.