Shift in oligosaccharide specificities of hemagglutinin and neuraminidase of influenza B viruses resistant to neuraminidase inhibitors |
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Authors: | Larisa Mochalova Rick Bright Xiyan Xu Elena Korchagina Alexander Chinarev Niсolai Bovin Alexander Klimov |
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Institution: | (1) Russian Academy of Sciences, Shemyakin and Ovchinnikov Institute of Bioorganic Chemistry, Miklukho-Maklaya 16/10, Moscow, 117997, Russia;(2) Present address: A.N. Belozersky Institute of Physico-Chemical Biology, M.V. Lomonosov Moscow State University, Leninskie Gory 1, Bldg. 40, Moscow, 119991, Russia;(3) Virus Surveillance and Diagnosis Branch, Influenza Division, NCIRD, CDC, Mail stop G-16, 1600 Clifton Rd, Atlanta, GA 30333, USA |
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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, α2-6-sialo-oligosaccharide
6`SLN, but desialylated it is approximately 8 times less efficiently than the α2-3 sialosaccharides. Both drug-resistant viruses
demonstrated the ability to bind to “avian type” receptors, α2-3 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. |
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