Restoration of HCV-specific T cell functions by PD-1/PD-L1 blockade in HCV infection: effect of viremia levels and antiviral treatment.
OBJECTIVE
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-alpha 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-alpha induced HCV-RNA decline, PD-L1 levels on dendritic cells increased during IFN-alpha 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-IFNalpha treatment.


CONCLUSIONS
PD-1/PD-L1 blockade has an immunoregulatory activity which may synergize with the antiviral effect of IFN-alpha therapy and should be thus explored further in long-lasting chronic HCV infections in the perspective of improving the efficacy of available antiviral treatments.
Urbani
Simona
S
Laboratory of Viral Immunopathology, Unit of Infectious Diseases and Hepatology, Italy.
Amadei
Barbara
B
Tola
Daniela
D
Pedrazzi
Giuseppe
G
Sacchelli
Luca
L
Cavallo
Maria Cristina
MC
Orlandini
Alessandra
A
Missale
Gabriele
G
Ferrari
Carlo
C
D015703:Antigens, CD / Q000187:drug effects* / Q000378:metabolism; D000998:Antiviral Agents / Q000627:therapeutic use*; D051017:Apoptosis Regulatory Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D060890:B7-H1 Antigen; D049109:Cell Proliferation / Q000187:drug effects; D003713:Dendritic Cells / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D005434:Flow Cytometry; D005500:Follow-Up Studies; D016174:Hepacivirus / Q000187:drug effects / Q000235:genetics / Q000276:immunology*; D018937:Hepatitis C Antibodies / Q000032:analysis / Q000276:immunology; D019698:Hepatitis C, Chronic / Q000188:drug therapy / Q000276:immunology / Q000821:virology*; D006801:Humans; D007371:Interferon-gamma / Q000627:therapeutic use; D061026:Programmed Cell Death 1 Receptor; D012367:RNA, Viral / Q000187:drug effects / Q000235:genetics; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology* / Q000473:pathology; D013997:Time Factors; D016896:Treatment Outcome; D014766:Viremia / Q000188:drug therapy / Q000276:immunology / Q000821:virology*
D015703:Antigens, CD; D000998:Antiviral Agents; D051017:Apoptosis Regulatory Proteins; D060890:B7-H1 Antigen; C423236:CD274 protein, human; D018937:Hepatitis C Antibodies; C105992:PDCD1 protein, human; D061026:Programmed Cell Death 1 Receptor; D012367:RNA, Viral; D007371:Interferon-gamma