title: Shift in oligosaccharide specificities of hemagglutinin and neuraminidase of influenza B viruses resistant to neuraminidase inhibitors.
abstract: Influenza virus neuraminidase inhibitors (NAIs), currently used as anti-influenza drugs, can lead to the appearance of drug-resistant variants. Resistance to NAIs appears due to mutations in the active site of the neuraminidase (NA) molecule that decrease the NA enzymatic activity and sometimes in the hemagglutinin (HA) that decrease its affinity for cell receptors and, therefore, reduce the requirement for NA activity in releasing mature virions from infected cells. Using a set of sialo-oligosaccharides, we evaluated changes in the receptor-binding specificity of the HA and substrate specificity of the NA of influenza B viruses that had acquired resistance to NAIs. The oligosaccharide specificity of two pairs of field influenza B viruses, namely: i) B/Memphis/20/96 and its NAI-resistant variant, B/Memphis/20-152K/96, containing mutation R152K in the NA and 5 amino acid substitutions in the HA1, and ii) B/Hong Kong/45/2005 and its NAI-resistant variant B/Hong Kong/36/2005, containing a single R371K mutation in the NA, was evaluated. Wild type viruses bound strictly to a "human type" receptor, alpha2-6-sialo-oligosaccharide 6;SLN, but desialylated it is approximately 8 times less efficiently than the alpha2-3 sialosaccharides. Both drug-resistant viruses demonstrated the ability to bind to "avian type" receptors, alpha2-3 sialo-oligosaccharides (such as 3;SLN), whereas their affinity for 6;SLN was noticeably reduced in comparison with corresponding wild type viruses. Thus, the development of the NAI resistance in the studied influenza B viruses was accompanied by a readjustment of HA-NA oligosaccharide specificities.
authors.affiliation: Russian Academy of Sciences, Shemyakin and Ovchinnikov Institute of Bioorganic Chemistry, Miklukho-Maklaya 16/10, Moscow, 117997, Russia. larisamochalova@gmail.com
authors.forename: Larisa
authors.initials: L
authors.lastname: Mochalova
authors.forename: Rick
authors.initials: R
authors.lastname: Bright
authors.forename: Xiyan
authors.initials: X
authors.lastname: Xu
authors.forename: Elena
authors.initials: E
authors.lastname: Korchagina
authors.forename: Alexander
authors.initials: A
authors.lastname: Chinarev
authors.forename: Nicolai
authors.initials: N
authors.lastname: Bovin
authors.forename: Alexander
authors.initials: A
authors.lastname: Klimov
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology; D002460:Cell Line; D004285:Dogs; D024882:Drug Resistance, Viral / Q000235:genetics; D006388:Hemagglutinins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D009981:Influenza B virus / Q000187:drug effects* / Q000201:enzymology* / Q000235:genetics; D009439:Neuraminidase / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D017433:Protein Structure, Secondary; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013379:Substrate Specificity
chemical_list: D000998:Antiviral Agents; D006388:Hemagglutinins; D009439:Neuraminidase