Glycoconjugate Journal

, Volume 27, Issue 3, pp 321–327 | Cite as

Shift in oligosaccharide specificities of hemagglutinin and neuraminidase of influenza B viruses resistant to neuraminidase inhibitors

  • Larisa Mochalova
  • Rick Bright
  • Xiyan Xu
  • Elena Korchagina
  • Alexander Chinarev
  • Niсolai Bovin
  • Alexander Klimov
Article

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.

Keywords

Influenza B virus Neuraminidase Neuraminidase inhibitor Drug resistance Hemagglutinin Receptor-binding specificity Neuraminidase substrate specificity 

Abbreviations

BODIPY FL

4,4-difluoro-5,7-dimethyl-4-bora-3a,4a-diaza-s-indacene-3-propionic acid

HA

hemagglutinin

HAU

hemagglutinating unit

HARI

inhibition of hemagglutination reaction

NA

neuraminidase

NAI

neuraminidase activity inhibitor

Neu5Ac

N-acetylneuraminic acid

OS-PAA

oligosaccharide-polyacrylamide conjugate

RBS

receptor-binding site

3`SLN

Neu5Acα2-3Galβ1-4GlcNAc

6`SLN

Neu5Acα2-6Galβ1-4GlcNAc

SLec

Neu5Acα2-3Galβ1-3GlcNAc

SLea

Neu5Acα2-3Galβ1-3(Fucα1-4)GlcNAc

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Copyright information

© Springer Science+Business Media, LLC 2010

Authors and Affiliations

  • Larisa Mochalova
    • 1
    • 2
  • Rick Bright
    • 3
  • Xiyan Xu
    • 3
  • Elena Korchagina
    • 1
  • Alexander Chinarev
    • 1
  • Niсolai Bovin
    • 1
  • Alexander Klimov
    • 3
  1. 1.Russian Academy of SciencesShemyakin and Ovchinnikov Institute of Bioorganic ChemistryMoscowRussia
  2. 2.A.N. Belozersky Institute of Physico-Chemical BiologyM.V. Lomonosov Moscow State UniversityMoscowRussia
  3. 3.Virus Surveillance and Diagnosis Branch, Influenza DivisionNCIRD, CDCAtlantaUSA

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