Gut. 2016 Dec;65(12):2029-2034. doi: 10.1136/gutjnl-2014-309045 Q125.82025

Targeting a host-cell entry factor barricades antiviral-resistant HCV variants from on-therapy breakthrough in human-liver mice

针对宿主细胞的入胞因子可使抗病毒耐药的HCV变异株无法在人肝鼠模型中突破疗法屏障翻译改进

Koen Vercauteren¹, Richard J P Brown², Ahmed Atef Mesalam¹, Juliane Doerrbecker², Sabin Bhuju³, Robert Geffers³, Naomi Van Den Eede¹, C Patrick McClure⁴, Fulvia Troise⁵, Lieven Verhoye¹, Thomas Baumert^{6 7}, Ali Farhoudi¹, Riccardo Cortese⁵, Jonathan K Ball⁴, Geert Leroux-Roels¹, Thomas Pietschmann^{2 8}, Alfredo Nicosia^{5 9}, Philip Meuleman¹

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作者单位

¹ Department Clinical Chemistry, Microbiology and Immunology, Center for Vaccinology, Ghent University, Ghent, Belgium.

² Institute of Experimental Virology, TWINCORE, Centre for Experimental and Clinical Infection Research; a joint venture between the Medical School Hannover (MHH) and the Helmholtz Centre for Infection Research (HZI), Hannover, Germany.

³ Genome Analytics, Helmholtz Centre for Infection Research, Braunschweig, Germany.

⁴ School of Life Sciences and the NIHR Nottingham Digestive Diseases Biomedical Research Unit, University of Nottingham, Queen's Medical Centre, Nottingham, UK.

⁵ CEINGE, Naples, Italy.

⁶ Institut National de la Santé et de la Recherche Médicale, U1110, Strasbourg, France.

⁷ Université de Strasbourg, Strasbourg et Pole Hépato-digestif, Hopitaux Universitaires de Strasbourg, Strasbourg, France.

⁸ German Centre for Infection Research (DZIF), Partner site Hannover-Braunschweig, Hannover, Germany.

⁹ Department of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, Naples, Italy.

DOI: 10.1136/gutjnl-2014-309045 PMID: 26306759

摘要 Ai翻译

Objective: Direct-acting antivirals (DAAs) inhibit hepatitis C virus (HCV) infection by targeting viral proteins that play essential roles in the replication process. However, selection of resistance-associated variants (RAVs) during DAA therapy has been a cause of therapeutic failure. In this study, we wished to address whether such RAVs could be controlled by the co-administration of host-targeting entry inhibitors that prevent intrahepatic viral spread.

Design: We investigated the effect of adding an entry inhibitor (the anti-scavenger receptor class B type I mAb1671) to a DAA monotherapy (the protease inhibitor ciluprevir) in human-liver mice chronically infected with HCV of genotype 1b. Clinically relevant non-laboratory strains were used to achieve viraemia consisting of a cloud of related viral variants (quasispecies) and the emergence of RAVs was monitored at high resolution using next-generation sequencing.

Results: HCV-infected human-liver mice receiving DAA monotherapy rapidly experienced on-therapy viral breakthrough. Deep sequencing of the HCV protease domain confirmed the manifestation of drug-resistant mutants upon viral rebound. In contrast, none of the mice treated with a combination of the DAA and the entry inhibitor experienced on-therapy viral breakthrough, despite detection of RAV emergence in some animals.

Conclusions: This study provides preclinical in vivo evidence that addition of an entry inhibitor to an anti-HCV DAA regimen restricts the breakthrough of DAA-resistant viruses. Our approach is an excellent strategy to prevent therapeutic failure caused by on-therapy rebound of DAA-RAVs. Inclusion of an entry inhibitor to the newest DAA combination therapies may further increase response rates, especially in difficult-to-treat patient populations.

Keywords: ANTIVIRAL THERAPY; CHRONIC VIRAL HEPATITIS; HCV; HEPATITIS C; LIVER.

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Keywords：host-cell entry factor

关键词：宿主细胞进入因子; 抗病毒耐药HCV变异体