Viral determinants in the NS3 helicase and 2K peptide that promote West Nile virus resistance to antiviral action of 2',5'-oligoadenylate synthetase 1b.
The interferon-inducible 2',5'-oligoadenylate synthetase 1b (Oas1b) protein inhibits West Nile virus (WNV) infection by preventing viral RNA (vRNA) accumulation in infected cells. Serial passage of WNV in Oas1b-expressing mouse cells selected a virus variant with improved growth capacity. Two major amino acid substitutions were identified in this Oas1b-resistant WNV variant: NS3-S365G in the ATPase/helicase domain of NS3 and 2K-V9M in the C-terminal segment of NS4A. To assess their effect on antiviral activity of Oas1b, the NS3 and 2K mutations were engineered into an infectious WNV cDNA clone. The NS3 mutation alters requirement of ATP for ATPase activity and attenuates Oas1b-mediated suppression of vRNA accumulation. However, growth of NS3-mutant virus remains impaired in Oas1b-expressing cells. Only the 2K-V9M mutation efficiently rescued viral growth by promoting vRNA replication. Thus, WNV resistance to Oas1b antiviral action could be attributed to the 2K-V9M substitution with a potential role of NS3-S365G through rescue of vRNA accumulation.
Mertens
Eva
E
Unité Interactions Moléculaires Flavivirus-Hôtes, Institut Pasteur, 75724 Paris, France.
Kajaste-Rudnitski
Anna
A
Unité Interactions Moléculaires Flavivirus-Hôtes, Institut Pasteur, 75724 Paris, France.
Torres
Shessy
S
Centre for Infectious Disease Research, School of Chemistry and Molecular Biosciences, University of Queensland, St. Lucia, Brisbane, Queensland 4072, Australia.
Funk
Anneke
A
Centre for Infectious Disease Research, School of Chemistry and Molecular Biosciences, University of Queensland, St. Lucia, Brisbane, Queensland 4072, Australia.
Frenkiel
Marie-Pascale
MP
Unité Interactions Moléculaires Flavivirus-Hôtes, Institut Pasteur, 75724 Paris, France.
Iteman
Isabelle
I
Plate-Forme Génotypage des Pathogènes et Santé Publique (PF-8), Institut Pasteur, 75724 Paris, France.
Khromykh
Alexander A
AA
Centre for Infectious Disease Research, School of Chemistry and Molecular Biosciences, University of Queensland, St. Lucia, Brisbane, Queensland 4072, Australia.
Desprès
Philippe
P
Unité Interactions Moléculaires Flavivirus-Hôtes, Institut Pasteur, 75724 Paris, France. Electronic address: philippe.despres@pasteur.fr.
D015088:2',5'-Oligoadenylate Synthetase / Q000494:pharmacology* / Q000502:physiology*; D019943:Amino Acid Substitution / Q000235:genetics; D000818:Animals; D004265:DNA Helicases / Q000378:metabolism / Q000502:physiology*; D004198:Disease Susceptibility; D015967:Gene Expression Regulation, Viral; D051379:Mice; D017354:Point Mutation / Q000235:genetics; D012367:RNA, Viral / Q000235:genetics; D014779:Virus Replication / Q000502:physiology; D014901:West Nile Fever / Q000188:drug therapy / Q000235:genetics / Q000821:virology; D014902:West Nile virus / Q000235:genetics / Q000472:pathogenicity* / Q000502:physiology
D012367:RNA, Viral; C509914:Oas1b protein, mouse; D015088:2',5'-Oligoadenylate Synthetase; D004265:DNA Helicases