Pegylated Interferon α-2a Triggers NK-Cell Functionality and Specific T-Cell Responses in Patients with Chronic HBV Infection without HBsAg Seroconversion

Juliana Bruder Costa; Tania Dufeu-Duchesne; Vincent Leroy; Inga Bertucci; Magali Bouvier-Alias; Noelle Pouget; Ophelie Brevot-Lutton; Marc Bourliere; Fabien Zoulim; Joel Plumas; Caroline Aspord; ANRS HB06 PEGAN study group

doi:10.1371/journal.pone.0158297

Pegylated Interferon α-2a Triggers NK-Cell Functionality and Specific T-Cell Responses in Patients with Chronic HBV Infection without HBsAg Seroconversion

PLoS One. 2016 Jun 27;11(6):e0158297. doi: 10.1371/journal.pone.0158297. eCollection 2016.

Authors

Juliana Bruder Costa^{1

2}, Tania Dufeu-Duchesne^{2

3}, Vincent Leroy^{2

3}, Inga Bertucci⁴, Magali Bouvier-Alias⁵, Noelle Pouget⁶, Ophelie Brevot-Lutton⁶, Marc Bourliere⁷, Fabien Zoulim^{8

9

10}, Joel Plumas^{1

11}, Caroline Aspord^{1

11}; ANRS HB06 PEGAN study group

Affiliations

¹ University Grenoble Alpes, Grenoble, F-38041 France; INSERM, U1209, Immunobiology and Immunotherapy of Chronic Deseases, La Tronche, F-38706 France.
² CHU Grenoble, Michallon Hospital, Hepato-gastroenterology unit, Grenoble, F-38043 France.
³ University Grenoble Alpes, Grenoble, F-38041 France; INSERM, U1209, Analytic Immunology of chronic pathologies, La Tronche, F-38706 France.
⁴ ANRS (France REcherche Nord & sud Sida-hiv Hépatites: FRENSH), Paris, France.
⁵ Department of Virology, Henri Mondor Hospital, University Paris-Est and Inserm U955, Creteil, France.
⁶ Sorbonne Universités, UPMC Univ Paris 06, INSERM, Institut Pierre Louis d'épidémiologie et de Santé Publique (IPLESP UMRS 1136), 75012, Paris, France.
⁷ Hepato-gastroenterology department Hospital Saint Joseph, Marseille, 13008 France.
⁸ INSERM U1052-CNRS 5286, Cancer Research Center of Lyon (CRCL), Lyon, France.
⁹ Hepatology Department, Hospices Civils de Lyon, Lyon, France.
¹⁰ Université de Lyon, Lyon, France.
¹¹ EFS Rhone-Alpes, R&D Laboratory, La Tronche, F-38701 France.

Abstract

Pegylated interferon α-2a (Peg-IFN-α) represents a therapeutic alternative to the prolonged use of nucleos(t)ide analog (NA) in chronic hepatitis B (CHB) infection. The mechanisms leading to a positive clinical outcome remain unclear. As immune responses are critical for virus control, we investigated the effects of Peg-IFN-α on both innate and adaptive immunity, and related it to the clinical evolution. The phenotypic and functional features of the dendritic cells (DCs), natural killer (NK) cells and HBV-specific CD4/CD8 T cells were analyzed in HBeAg-negative CHB patients treated for 48-weeks with NA alone or together with Peg-IFN-α, before, during and up to 2-years after therapy. Peg-IFN-α induced an early activation of DCs, a potent expansion of the CD56bright NK subset, and enhanced the activation and functionality of the CD56dim NK subset. Peg-IFN-α triggered an increase in the frequencies of Th1- and Th17-oriented HBV-specific CD4/CD8 T cells. Peg-IFN-α reversed the unresponsiveness of patients to a specific stimulation. Most of the parameters returned to baseline after the stop of Peg-IFN-α therapy. Peg-IFN-α impacts both innate and adaptive immunity, overcoming dysfunctional immune responses in CHB patients. These modulations were not associated with seroconversion, which questioned the benefit of the add-on Peg-IFN-α treatment.

MeSH terms

Adult
Aged
Biomarkers
DNA, Viral
Dendritic Cells / drug effects
Dendritic Cells / immunology
Dendritic Cells / metabolism
Female
Hepatitis B Surface Antigens / blood
Hepatitis B Surface Antigens / immunology*
Hepatitis B, Chronic / blood
Hepatitis B, Chronic / drug therapy
Hepatitis B, Chronic / immunology*
Hepatitis B, Chronic / virology
Humans
Interferon-alpha / pharmacology*
Interferon-alpha / therapeutic use
Killer Cells, Natural / drug effects*
Killer Cells, Natural / immunology*
Killer Cells, Natural / metabolism
Liver Function Tests
Lymphocyte Activation / immunology
Male
Middle Aged
Phenotype
Polyethylene Glycols / pharmacology*
Polyethylene Glycols / therapeutic use
Recombinant Proteins / pharmacology
Recombinant Proteins / therapeutic use
T-Cell Antigen Receptor Specificity / immunology*
T-Lymphocyte Subsets / drug effects
T-Lymphocyte Subsets / immunology
T-Lymphocyte Subsets / metabolism
T-Lymphocytes / drug effects*
T-Lymphocytes / immunology*
T-Lymphocytes / metabolism
Treatment Outcome
Viral Load

Substances

Biomarkers
DNA, Viral
Hepatitis B Surface Antigens
Interferon-alpha
Recombinant Proteins
Polyethylene Glycols
peginterferon alfa-2a

Grants and funding

This work was supported by the French Blood Service (EFS) and the study was sponsored and funded by ANRS(France REcherche Nord & sud Sida-hiv Hépatites).