Antiviral resistance among highly pathogenic influenza A (H5N1) viruses isolated worldwide in 2002–2012 shows need for continued monitoring

Abstract

Highly pathogenic (HP) H5N1 influenza viruses are evolving pathogens with the potential to cause sustained human-to-human transmission and pandemic virus spread. Specific antiviral drugs can play an important role in the early stages of a pandemic, but the emergence of drug-resistant variants can limit control options. The available data on the susceptibility of HP H5N1 influenza viruses to neuraminidase (NA) inhibitors and adamantanes is scarce, and there is no extensive analysis. Here, we systematically examined the prevalence of NA inhibitor and adamantane resistance among HP H5N1 influenza viruses that circulated worldwide during 2002–2012. The phenotypic fluorescence-based assay showed that both human and avian HP H5N1 viruses are susceptible to NA inhibitors oseltamivir and zanamivir with little variability over time and ~5.5-fold less susceptibility to oseltamivir of viruses of hemagglutinin (HA) clade 2 than of clade 1. Analysis of available sequence data revealed a low incidence of NA inhibitor–resistant variants. The established markers of NA inhibitor resistance (E119A, H274Y, and N294S, N2 numbering) were found in 2.4% of human and 0.8% of avian isolates, and the markers of reduced susceptibility (I117V, K150N, I222V/T/K, and S246N) were found in 0.8% of human and 2.9 % of avian isolates. The frequency of amantadine-resistant variants was higher among human (62.2%) than avian (31.6%) viruses with disproportionate distribution among different HA clades. As in human isolates, avian H5N1 viruses carry double L26I and S31N M2 mutations more often than a single S31N mutation. Overall, both human and avian HP H5N1 influenza viruses are susceptible to NA inhibitors; some proportion is still susceptible to amantadine in contrast to ~100% amantadine resistance among currently circulating seasonal human H1N1 and H3N2 viruses. Continued antiviral susceptibility monitoring of H5N1 viruses is needed to maintain therapeutic approaches for control of disease.

Inhibition of Reactive Oxygen Species Production Ameliorates Inflammation Induced by Influenza A Viruses via Upregulation of SOCS1 and SOCS3

“…These results, along with others, have contributed to an increased focus on the development of intervention strategies with the ability to modulate deleterious host immune responses, such as those triggered by ROS, in an attempt to ameliorate disease severity (9). This is particularly important given the documentation of H5N1 and H7N9 influenza virus antiviral drug resistance (2,13). The data presented here provide important mechanistic evidence to suggest that apocynin or its derivatives could be used therapeutically to reduce immunopathology following H5N1 or H7N9 avian virus infection, resulting in amelioration of disease severity.…”

Detection of Proton Movement Directly across Viral Membranes To Identify Novel Influenza Virus M2 Inhibitors

“…Two FDA-approved adamantane-based drugs, amantadine and rimantadine (2,8), are potent M2 inhibitors that can neutralize influenza virus in humans and other animals. However, the emergence of widespread highly virulent adamantane-resistant strains such as avian and swine influenza virus strains (9,10) has prompted the need for newer antivirals. Drug discovery efforts targeting M2 have been difficult due to the toxicity of M2 in cells (11), the difficulty of reconstituting M2 in liposomes for largescale application (12,13), and the labor-intensive, low-throughput electrophysiological approaches typically used to study ion channels.…”

Genetic characterization of an H5N1 avian influenza virus from a vaccinated duck flock in Vietnam

“…The analysis of predicted amino acid sequence for the NA of Dk/VN/QB1207/12 and representative Vietnamese strains did not identify any of the amino acid substitutions known to relate to the oseltamivir resistance (Table 4) [35,36]. In the M2 protein of Dk/VN/QB1207/12, the S31A mutation known to be involved in amantadine resistance was also not seen.…”

“…However, the M2 of Dk/VN/QB1207/12 contained an amino acid substitution at position 27 (V27I), which may suggest a reduced susceptibility to amantadine (Table 4) [37,38]. Recently, Govorkova et al [36] systematically examined the prevalence of NA inhibitor and amantadine resistance among the HPAIVs circulating worldwide, and reported that most of the HPAIVs are likely to be susceptible to NA inhibitors while some proportion will also be susceptible to amantadine. The genetic features of Dk/VN/QB1207/12 seem to match that prediction.…”