Antiviral Res. 2018 Nov 12. pii: S0166-3542(18)30452-2. doi: 10.1016/j.antiviral.2018.11.003. [Epub ahead of print]
PASylated interferon α efficiently suppresses hepatitis B virus and induces anti-HBs seroconversion in HBV-transgenic mice.
Xia Y1, Schlapschy M2, Morath V2, Roeder N3, Vogt EI2, Stadler D1, Cheng X1, Dittmer U4, Sutter K4, Heikenwalder M1, Skerra A5, Protzer U6.
Author information
1
Institute of Virology, Technische Universität München/Helmholtz Zentrum München, 81675, Munich, Germany.
2
Munich Center for Integrated Protein Science (CIPS-M) and Lehrstuhl für Biologische Chemie, Technische Universität München, 85354, Freising, Weihenstephan, Germany.
3
Institute of Virology, Technische Universität München/Helmholtz Zentrum München, 81675, Munich, Germany; German Center for Infection Research (DZIF), Munich Partner Site, 81675, Munich, Germany.
4
Institute for Virology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany.
5
Munich Center for Integrated Protein Science (CIPS-M) and Lehrstuhl für Biologische Chemie, Technische Universität München, 85354, Freising, Weihenstephan, Germany. Electronic address: [email protected].
6
Institute of Virology, Technische Universität München/Helmholtz Zentrum München, 81675, Munich, Germany; German Center for Infection Research (DZIF), Munich Partner Site, 81675, Munich, Germany. Electronic address: [email protected].
Abstract
Interferon α (IFNα) so far is the only therapeutic option for chronic hepatitis B virus (HBV) infection that can lead to virus clearance. Unfortunately, its application is limited by side effects and response rates are low. The aim of this study was to generate a novel long-acting IFNα with the help of PASylation technology that adds a polypeptide comprising Proline, Alanine and Serine (PAS) to increase protein half-life. Following evaluation of four selected recombinant murine IFNα (mIFNα) subtypes in cell culture, the most active subtype mIFNα11 was fused with a 600 amino acid PAS-residue. The activity of PAS-mIFNα was assessed by interferon bioassay and further evaluated for induction of interferon-stimulated genes (ISG) and antiviral efficacy in cell culture and HBV-transgenic mice. PAS-mIFNα induced expression of ISG comparable to unmodified mIFNα and, likewise, evoked dose-dependent reduction of HBV replication in vitro. In vivo, PAS-mIFNα led to pronounced suppression of HBV replication without detectable liver damage whereas conventional mIFNα treatment only had a modest antiviral effect. Importantly, all PAS-mIFNα treated mice showed an anti-HBs antibody response, lost HBsAg and achieved seroconversion after three weeks. PASylated IFNα showed a profoundly increased antiviral effect in vivo compared to the non-modified version without toxicity, providing proof-of-concept that an improved IFNα can achieve higher rates of HBV antiviral and immune control.
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