title: Natural HCV variants with increased replicative fitness due to NS3 helicase mutations in the C-terminal helix α18.
abstract: High replicative fitness is a general determinant of a multidrug resistance phenotype and may explain lower sensitivity to direct-acting antiviral agents (DAAs) in some hepatitis C virus genotypes. Genetic diversity in the molecular target site of peptidomimetic NS3 protease inhibitors could impact variant replicative fitness and potentially add to virologic treatment failure. We selected NS3 helicase residues near the protease natural substrate in the NS3 domain interface and identified natural variants from a public database. Sequence diversity among different genotypes was identified and subsequently analyzed for potential effects of helicase variants on protein structure and function, and phenotypic effects on RNA replication and DAA resistance. We found increased replicative fitness in particular for amino acid substitutions at the NS3 helicase C-terminal helix α18. A network of strongly coupled residue pairs is identified. Helix α18 is part of this regulatory network and connects several NS3 functional elements involved in RNA replication. Among all genotypes we found distinct sequence diversity at helix α18 in particular for the most difficult-to-treat genotype 3. Our data suggest sequence diversity with implications for virus replicative fitness due to natural variants in helicase helix α18.
authors.affiliation: Department of Internal Medicine 1, Goethe University Hospital Frankfurt, 60590 Frankfurt a.M., Germany.
authors.forename: Claudia
authors.initials: C
authors.lastname: Stross
authors.affiliation: Department of Gastroenterology, Kanazawa University Hospital, Kanazawa, Japan.
authors.forename: Tetsuro
authors.initials: T
authors.lastname: Shimakami
authors.affiliation: Department of Internal Medicine 1, Goethe University Hospital Frankfurt, 60590 Frankfurt a.M., Germany.
authors.forename: Katrin
authors.initials: K
authors.lastname: Haselow
authors.affiliation: Department of Internal Medicine 1, Goethe University Hospital Frankfurt, 60590 Frankfurt a.M., Germany.
authors.forename: Monazza Q
authors.initials: MQ
authors.lastname: Ahmad
authors.affiliation: Department of Internal Medicine 1, Goethe University Hospital Frankfurt, 60590 Frankfurt a.M., Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Zeuzem
authors.affiliation: Department of Internal Medicine 1, Goethe University Hospital Frankfurt, 60590 Frankfurt a.M., Germany.
authors.forename: Christian M
authors.initials: CM
authors.lastname: Lange
authors.affiliation: Department of Internal Medicine 1, Goethe University Hospital Frankfurt, 60590 Frankfurt a.M., Germany.
authors.forename: Christoph
authors.initials: C
authors.lastname: Welsch
mesh_terms: D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D000998:Antiviral Agents / Q000494:pharmacology; D024882:Drug Resistance, Viral; D056084:Genetic Fitness; D014644:Genetic Variation; D005838:Genotype; D016174:Hepacivirus / Q000187:drug effects / Q000502:physiology*; D006801:Humans; D008958:Models, Molecular; D009154:Mutation; D056510:Position-Specific Scoring Matrices; D011480:Protease Inhibitors / Q000494:pharmacology; D011487:Protein Conformation; D054730:Protein Interaction Domains and Motifs / Q000235:genetics*; D012367:RNA, Viral / Q000235:genetics; D013329:Structure-Activity Relationship; D017361:Viral Nonstructural Proteins / Q000737:chemistry* / Q000235:genetics*; D014779:Virus Replication; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases
chemical_list: D000998:Antiviral Agents; D011480:Protease Inhibitors; D012367:RNA, Viral; D017361:Viral Nonstructural Proteins; C084422:NS3 protein, hepatitis C virus; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases