Journal
JOURNAL OF MOLECULAR BIOLOGY
Volume 431, Issue 12, Pages 2354-2368Publisher
ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD
DOI: 10.1016/j.jmb.2019.04.034
Keywords
hepatitis C virus; subtype; viral variant fitness; residue networks; molecular determinants
Categories
Funding
- Max Planck Society
- Cluster of Excellence for Multimodal Computing and Interaction (MMCI)
- Department of Innovation, Research, Development and Cooperatives, Autonomous Province of Bolzano-South Tyrol
- BioTechMed-Graz
- German Research Foundation [WE 4388/6-1]
- JSPS-DAAD under the Japan-Germany Research Cooperative Program
- National Institutes of Allergy and Infectious Diseases [R21-AI115207]
- Landes-Offensive zur Entwicklung Wissenschaftlich-okonomischer Exzellenz (LOEWE) of the State of Hessen Research Center for Translational Medicine and Pharmacology TMP
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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.
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