Adamantane-Resistant Influenza A Viruses in the World (1902–2013): Frequency and Distribution of M2 Gene Mutations

Abstract

Adamantanes (amantadine and rimantadine) have been used to prevent and treat influenza A virus infections for many years; however, resistance to these drugs has been widely reported in the world. To investigate the frequency and distribution of M2 gene mutations in adamantane-resistant influenza variants circulated in the world between 1902 and 2013, 31251 available M2 protein sequences from different HA-subtype influenza A viruses (H1–H17) were analyzed and adamantane resistance-associated mutations were compared (L26F, V27A, A30T, A30V, S31N, G34E, and L38F). We find that 45.2% (n = 14132) of influenza A (H1–H17) viruses circulating globally were resistant to adamantanes, and the vast majority of resistant viruses (95%) bear S31N mutations. Whereas, only about 1% have V27A mutations and other mutations (L26F, A30T, G34E, and L38F) were extremely rare (their prevalence appeared to be < 0.2%). Our results confirm that H1, H3, H5, H7, H9, and H17 subtype influenza A viruses exhibit high-level resistance to adamantanes. In contrast, the appearance of adamantane-resistant mutants in H2, H4, H6, H10, and H11 subtypes was rare. However, no adamantane resistance viruses were identified among other HA subtypes (H8, H12–H16). Our findings indicate that the frequency and distribution of adamantane-resistant influenza variants varied among different HA subtypes, host species, years of isolation, and geographical areas. This comprehensive study raises concerns about the increasing prevalence of adamantane-resistant influenza A viruses and highlights the importance of monitoring the emergence and worldwide spread of adamantane-resistant variants.

The E119D neuraminidase mutation identified in a multidrug-resistant influenza A(H1N1)pdm09 isolate severely alters viral fitness in vitro and in animal models

“…Consequently, antiviral agents are particularly needed for the management of influenza in such situations. In this regard, neuraminidase inhibitors (NAIs) constitute the antiviral class of choice (Moscona, 2005) as most seasonal A/H3N2 viruses isolated after 2005 and all A(H1N1) pdm09 viruses have been shown to be resistant to the adamantanes (amantadine and rimantadine) (Dong et al, 2015). NAIs target the active center of the influenza neuraminidase (NA) molecule, which is made of 8 functional (R-118, D-151, R-152, R-224, E-276, R-292, R-371, and Y-406; N2 numbering) and 11 framework and EÀ425;N2 numbering) residues that are largely conserved among influenza A and B viruses (Colman et al, 1993).…”

Levels of Antiviral Therapy

“…Thus 93.2% of the strains of influenza A virus (H3N2) and 88.9% of the strains of influenza A virus (H1N1) had the amino acid substitution on position 31 of M2-channel gene. A similar frequency of resistance to the influenza A virus H3N2 (100% in 2010) was observed during this period in Canada [2,35].…”

“…The frequency of resistance was the highest in Asia and in Central Africa. There were 96.8% resistant isolates in China in 2008 and 100.0% resistant isolates in Kenya and Uganda [35]. A high frequency of resistance to amantadine of influenza A isolates was also observed in the United States at season 2012-2013.…”

Thematic Review Series: Phospholipases: Central Role in Lipid Signaling and Disease

“…As a consequence, treatment and prevention measures for infl uenza virus infections remain challenging. For example, in this current fl u season, for which the immunization cocktail was largely ineffective through being directed at the incorrect strains, the anti-infl uenza therapeutic amantadine was also found to be of relatively little benefi t due to extensive acquired viral resistance to it ( 72 ), suggesting the need for new therapeutic approaches. A genome-wide RNA interference screen identifi ed 287 human host cell genes that infl uence the viruses' ability to replicate, of which 29 were required N-terminal transmembrane domain and a short cytoplasmic sequence, with the putative catalytic domain localizing to the lumen of the ER ( 29 ) ( Fig.…”