Neuraminidase inhibitor resistance in influenza viruses and laboratory testing methods

Abstract

Infection with influenza viruses, including seasonal, avian and pandemic viruses, remains a worldwide public health problem. Although influenza virus infection is both vaccine preventable and drug treatable, high rates of mutation and reassortment of viruses can result in reduced effectiveness of vaccines or drugs. Currently, two classes of drugs, adamantanes (M2 blockers) and neuraminidase (NA) inhibitors (NAIs), are available for treatment and chemoprophylaxis of influenza infections. Given these limited antiviral therapy options, resistance to anti-influenza drugs is a constant concern. The emergence and global spread of adamantane-resistant H3N2 viruses in 2003-2004 and oseltamivir-resistant seasonal H1N1 viruses in 2007-2009 demonstrated the ability of drug-resistant variants to rapidly become predominant worldwide. Since the 2009 H1N1 pandemic, all influenza viruses circulating in humans are M2-blocker-resistant and, in general, NAI-susceptible. However, pandemic H1N1 viruses with resistance to the NAI oseltamivir have been reported. 'Permissive' drift mutations and reassortment of viral gene segments have been proposed as mechanisms underlying the retained replicative fitness of resistant viruses. Nevertheless, the precise role of these genetic changes in the efficient transmission and maintenance of resistant viruses in the absence of drug pressure remains poorly understood. In this review, we summarize NAI resistance in influenza viruses and discuss recent challenges in laboratory testing methods. Close monitoring of antiviral resistance among all influenza viruses, both locally and globally, are essential to inform public health strategies for the control of influenza infections.

Genesis and Dissemination of Highly Pathogenic H5N6 Avian Influenza Viruses

“…The reassortant C isolates carried a deletion at position 126 in the HA, adding a potential N-glycosylation at site 124. The R152K mutation in the NA in Yunnan human isolates may affect susceptibility to inhibitors (25). Mutations E627K and D701N, which that enhanced virulence in mammals, were found in the PB2 protein of human isolates (26).…”

Detection of influenza B viruses with reduced sensitivity to neuraminidase inhibitor in Morocco during 2014/15 season

“…B/Morocco/CP10/2015 and B/ Morocco/176H/2015 showing reduced sensitivity to oseltamivir did not harbour any substitution mutations known to confer reduced sensitivity to influenza B strains, such as G109E, G402S, D198N and I221T detected in isolates from patients treated with NAIs (2,8). However, B/Morocco/ CP10/2015 harboured amino acid substitution K371N (B numbering) located among the highly conserved catalytic NA residues.…”

“…This could be explained by the characteristic structure and conformation of this drug. The higher structural homology with the NA natural substrate, sialic acid, and lower use of zanamivir (compared with oseltamivir) are the most probable factors to account for the infrequent isolation of zanamivirresistant variants worldwide (8).…”

“…A later study among 346 influenza B viruses isolated worldwide during 2011 identified 2 (0.6%) with reduced susceptibility to NAIs (6). These resistant viruses can emerge under drug selection pressure or occur naturally without drug interventions (7), and are associated with amino acid substitutions at the conserved NA residues or in surrounding locations (8).…”

Between Artemisinin and Derivatives With Neuraminidase: A Docking Study Insight

“…However, since almost every known NAIs share similar molecular structure, the potency of crossresistances between NAIs is still high [9,10]. Discovery of secondary metabolites from medicinal plants with antiviral especially antiinfluenza activity is a key to obtain new NAI with high effectiveness.…”