Near-Neighbor Interactions in the NS3-4A Protease of HCV Impact Replicative Fitness of Drug-Resistant Viral Variants

JOURNAL OF MOLECULAR BIOLOGY

卷:431

Article

Doncheva, Nadezhda T.^1,2,8,9  Domingues, Francisco S.³  McGivern, David R.^4,10  Shimakami, Tetsuro⁵  Zeuzem, Stefan⁶  Lengauer, Thomas¹  Lange, Christian M.⁶  Albrecht, Mario⁷  Welsch, Christoph^1,6 

[1] Max Planck Inst Informat, Dept Computat Biol & Appl Algorithm, Saarbrucken, Germany

[2] Saarland Univ, Grad Sch Comp Sci, Saarbrucken, Germany

[3] European Acad Bozen Bolzano EURAC, Ctr Biomed, Bolzano, Italy

[4] Univ N Carolina, Dept Med, Div Infect Dis, Chapel Hill, NC 27599 USA

[5] Kanazawa Univ Hosp, Dept Gastroenterol, Kanazawa, Ishikawa, Japan

[6] Goethe Univ Hosp Frankfurt, Dept Internal Med 1, Frankfurt, Germany

[7] Graz Univ Technol, Inst Knowledge Discovery, Graz, Austria

[8] Univ Copenhagen, Dept Vet & Anim Sci, Ctr Noncoding RNA Technol & Hlth, Copenhagen, Denmark

[9] Univ Copenhagen, Dept Vet & Anim Sci, NNF Ctr Prot Res, Copenhagen, Denmark

[10] US FDA, Ctr Biol Evaluat & Res, Silver Spring, MD USA

关键词: hepatitis C virus;    subtype;    viral variant fitness;    residue networks;    molecular determinants;   

DOI  :  10.1016/j.jmb.2019.04.034

来源: Elsevier

【 摘 要 】

A variety of amino acid substitutions in the NS3-4A protease of the hepatitis C virus lead to protease inhibitor (PI) resistance. Many of these significantly impair the replication fitness of the resistant variants in a genotype-and subtype-dependent manner, a critical factor in determining the probability with which resistant variants will persist. However, the underlying molecular mechanisms are unknown. Here, we present a novel residue interaction network approach to determine how near-neighbor interactions of PI resistance mutations in NS3-4A can impact protease functional sites dependent on their genomic background. We constructed subtype-specific consensus residue networks for subtypes la and 1b from protease structure ensembles combined with biological properties of protein residues and evolutionary amino acid conservation. By applying local and global network topology analysis and visual exploration, we characterize PI resistance-associated sites and outline differences in near-neighbor interactions. We find local residue-interaction patterns and features at protease functional sites that are subtype specific. The noncovalent bonding patterns indicate higher fitness costs conferred by PI resistance mutations in a subtype 1b genomic background and explain the prevalence of Q80K and R155K in subtype I a. Based on local residue interactions, we predict a subtype-specific role for the protease residue NS3-Q80 in molecular mechanisms related to the assembly of infectious virus particles that is supported by experimental data on the capacity of Q80K variants to replicate and produce infectious virus in subtype la and 1b cell culture. (C) 2019 Elsevier Ltd. All rights reserved.

【 授权许可】

Free