The Genesis and Spread of Reassortment Human Influenza A/H3N2 Viruses Conferring Adamantane Resistance

Simonsen, Lone; Viboud, Cécile; Grenfell, Bryan T.; Dushoff, Jonathan; Jennings, Lance C.; Smit, Marita; Macken, Catherine A.; Hata, Mami; Gog, Julia R.; Miller, Mark A.; Holmes, Edward C.

doi:10.1093/molbev/msm103

Cited by 176 publications

(189 citation statements)

References 30 publications

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“…As most of these resistance strains have the same substitution (Ser31Asn for the M2 gene of A/H3N2 viruses) and antiviral agents are not commonly used in this region, a common origin for these viruses is a strong possibility 23 . In agreement to previously published data, 24 these findings suggest that these resistant variants could have arisen in the absence of any antiviral selective pressure, or if they have a common origin in places where antiviral agents are used, they must have an advantage for their maintenance even in the absence of these agents that contributed to their migration, global distribution and maintenance over a 3 year period.…”

Section: Resultssupporting

confidence: 91%

Antiviral resistance in influenza viruses circulating in Central and South America based on the detection of established genetic markers

Garcia

Sovero

Torres

et al. 2009

Influenza Resp Viruses

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Background Recent influenza antiviral resistance studies reveal an alarming increase in both adamantanes and neuraminidase inhibitors (NAIs) resistant viral strains worldwide, particularly in Asia, Europe and the United States. Objectives In this study, we have evaluated influenza virus resistance in Central and South America. Methods Influenza viruses, isolated from symptomatic patients throughout Central and South America in 2005–2008 were analyzed for inhibitor resistance. The M2 and NA genes of influenza viruses were sequenced and resistance was inferred by comparison with published sequences and known resistant mutations. Results Our results indicate that: (i) resistance to adamantanes was seen in the majority (95·5%) of the influenza A/H3N2 isolates but only in one isolate of the influenza A/H1N1 viruses; (ii) resistance to NAIs began to be detected in A/H1N1 isolates from Central America in 2008; and (iii) none of the influenza B viruses analyzed were resistant to NAIs. Conclusions These findings suggest a limited effectiveness of influenza inhibitors due to the detection of resistance among A/H1 and A/H3 viruses.

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Section: Resultssupporting

confidence: 91%

Antiviral resistance in influenza viruses circulating in Central and South America based on the detection of established genetic markers

Garcia

Sovero

Torres

et al. 2009

Influenza Resp Viruses

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“…Indeed, large-scale sequencing of transmissible viruses isolated as early as 1918 showed that mutations to pore-lining residues are allowed only within the first turn of the transmembrane (TM) helix at positions 26, 27, and 31 (10). S31N has long been the predominant amantadine-resistant mutation in M2 (11)(12)(13)(14). It predominated in 98-100% of the transmissible amantadineresistant H1N1, H5N1, and H3N2 strains isolated from humans, birds, and swine in the past decade.…”

Section: M2-s31n Inhibitormentioning

confidence: 99%

Structure and inhibition of the drug-resistant S31N mutant of the M2 ion channel of influenza A virus

Wang

Ma³

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

203

350

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The influenza A virus M2 proton channel (A/M2) is the target of the antiviral drugs amantadine and rimantadine, whose use has been discontinued due to widespread drug resistance. Among the handful of drug-resistant mutants, S31N is found in more than 95% of the currently circulating viruses and shows greatly decreased inhibition by amantadine. The discovery of inhibitors of S31N has been hampered by the limited size, polarity, and dynamic nature of its amantadine-binding site. Nevertheless, we have discovered smallmolecule drugs that inhibit S31N with potencies greater than amantadine's potency against WT M2. Drug binding locks the protein into a well-defined conformation, and the NMR structure of the complex shows the drug bound in the homotetrameric channel, threaded between the side chains of Asn31. Unrestrained molecular dynamics simulations predicted the same binding site. This S31N inhibitor, like other potent M2 inhibitors, contains a charged ammonium group. The ammonium binds as a hydrate to one of three sites aligned along the central cavity that appear to be hotspots for inhibition. These sites might stabilize hydronium-like species formed as protons diffuse through the outer channel to the proton-shuttling residue His37 near the cytoplasmic end of the channel.M2-S31N mutant structure | membrane protein structure | M2-S31N inhibitorT he influenza A virus M2 proton channel (A/M2) is the target of the antiviral drugs amantadine and rimantadine (1-3), which bind directly to the pore of the channel (2-4). Although amantadine has been widely used for several decades, drug resistance has curtailed the use of this family of drugs. Many amantadineresistant influenza viruses can be selected in cell culture (5, 6). A subset of these mutations is found in infected patients undergoing treatment with amantadine (7), and reverse-engineered viruses harboring various pore-lining mutations are competent to replicate in the mouse (8). However, many of these mutations give rise to somewhat attenuated viruses that are less transmissible than WT virus, and they tend to revert in the absence of drug pressure (6, 9). Indeed, large-scale sequencing of transmissible viruses isolated as early as 1918 showed that mutations to pore-lining residues are allowed only within the first turn of the transmembrane (TM) helix at positions 26, 27, and 31 (10). S31N has long been the predominant amantadine-resistant mutation in M2 (11)(12)(13)(14). It predominated in 98-100% of the transmissible amantadineresistant H1N1, H5N1, and H3N2 strains isolated from humans, birds, and swine in the past decade. V27A and L26F are less frequent mutations (10,11,15). Extensive studies of point mutations to the pore-lining residues of M2 have been conducted to understand the paucity of natural variants (16,17). Numerous mutants in the N-terminal aqueous pore retained the ability to conduct protons selectively over other ions, although the magnitude and pH dependence of their conduction varied. However, only a few mutations at the most distal sites, V27A,...

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“…1(A)]. S31N has long been the dominant amantadine-resistant mutation in M2, [46][47][48][49] accounting for 98-100%…”

Section: Natural and Artificial Sequence Variants Of M2mentioning

confidence: 99%

Structural basis for proton conduction and inhibition by the influenza M2 protein

2012

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The influenza M2 protein forms an acid-activated and drug-sensitive proton channel in the virus envelope that is important for the virus lifecycle. The functional properties and high-resolution structures of this proton channel have been extensively studied to understand the mechanisms of proton conduction and drug inhibition. We review biochemical and electrophysiological studies of M2 and discuss how high-resolution structures have transformed our understanding of this proton channel. Comparison of structures obtained in different membrane-mimetic solvents and under different pH using X-ray crystallography, solution NMR, and solid-state NMR spectroscopy revealed how the M2 structure depends on the environment and showed that the pharmacologically relevant drug-binding site lies in the transmembrane (TM) pore. Competing models of proton conduction have been evaluated using biochemical experiments, high-resolution structural methods, and computational modeling. These results are converging to a model in which a histidine residue in the TM domain mediates proton relay with water, aided by microsecond conformational dynamics of the imidazole ring. These mechanistic insights are guiding the design of new inhibitors that target drug-resistant M2 variants and may be relevant for other proton channels.

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The Genesis and Spread of Reassortment Human Influenza A/H3N2 Viruses Conferring Adamantane Resistance

Cited by 176 publications

References 30 publications

Antiviral resistance in influenza viruses circulating in Central and South America based on the detection of established genetic markers

Antiviral resistance in influenza viruses circulating in Central and South America based on the detection of established genetic markers

Structure and inhibition of the drug-resistant S31N mutant of the M2 ion channel of influenza A virus

Structural basis for proton conduction and inhibition by the influenza M2 protein

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