The genesis and spread of reassortment human influenza A/H3N2 viruses conferring adamantane resistance

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

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

Resumé

A dramatic rise in the frequency of resistance to adamantane drugs by influenza A (H3N2) viruses has occurred in recent years -- from approximately 2% to approximately 90% in multiple countries worldwide-and associated with a single S31N amino acid replacement in the viral matrix M2 protein. To explore the emergence and spread of these adamantane resistant viruses we performed a phylogenetic analysis of recently sampled complete A/H3N2 genome sequences. Strikingly, all adamantane resistant viruses belonged to a single lineage (the "N-lineage") characterized by 17 amino acid replacements across the viral genome. Further, our analysis revealed that the genesis of the N-lineage was due to a 4+4 segment reassortment event involving 2 distinct lineages of influenza A/H3N2 virus. A subsequent study of hemagglutinin HA1 sequences suggested that the N-lineage was circulating widely in Asia during 2005, and then dominated the Northern hemisphere 2005-2006 season in Japan and the USA. Given the infrequent use of adamantane drugs in many countries, as well as the decades of use in the US associated with little drug resistance, we propose that the globally increasing frequency of adamantane resistance is more likely attributable to its interaction with fitness-enhancing mutations at other genomic sites rather than to direct drug selection pressure. This implies that adamantanes may not be useful for treatment and prophylaxis against influenza viruses in the long term. More generally, these findings illustrate that drug selection pressure is not the sole factor determining the evolution and maintenance of drug resistance in human pathogens.
OriginalsprogEngelsk
TidsskriftMolecular Biology and Evolution
Vol/bind24
Udgave nummer8
Sider (fra-til)1811-1820
ISSN0737-4038
StatusUdgivet - 2007

Citer dette

Simonsen, L., Viboud, C., Grenfell, B. T., Dushoff, J., Jennings, L., Smit, M., ... Holmes, E. C. (2007). The genesis and spread of reassortment human influenza A/H3N2 viruses conferring adamantane resistance. Molecular Biology and Evolution, 24(8), 1811-1820.
Simonsen, Lone ; Viboud, Cecile ; Grenfell, Bryan T. ; Dushoff, Jonathan ; Jennings, Lance ; Smit, Marita ; Macken, Catherine ; Hata, Mami ; Gog, Julia ; Miller, Mark ; Holmes, Edward C. / The genesis and spread of reassortment human influenza A/H3N2 viruses conferring adamantane resistance. I: Molecular Biology and Evolution. 2007 ; Bind 24, Nr. 8. s. 1811-1820.
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title = "The genesis and spread of reassortment human influenza A/H3N2 viruses conferring adamantane resistance",
abstract = "A dramatic rise in the frequency of resistance to adamantane drugs by influenza A (H3N2) viruses has occurred in recent years -- from approximately 2{\%} to approximately 90{\%} in multiple countries worldwide-and associated with a single S31N amino acid replacement in the viral matrix M2 protein. To explore the emergence and spread of these adamantane resistant viruses we performed a phylogenetic analysis of recently sampled complete A/H3N2 genome sequences. Strikingly, all adamantane resistant viruses belonged to a single lineage (the {"}N-lineage{"}) characterized by 17 amino acid replacements across the viral genome. Further, our analysis revealed that the genesis of the N-lineage was due to a 4+4 segment reassortment event involving 2 distinct lineages of influenza A/H3N2 virus. A subsequent study of hemagglutinin HA1 sequences suggested that the N-lineage was circulating widely in Asia during 2005, and then dominated the Northern hemisphere 2005-2006 season in Japan and the USA. Given the infrequent use of adamantane drugs in many countries, as well as the decades of use in the US associated with little drug resistance, we propose that the globally increasing frequency of adamantane resistance is more likely attributable to its interaction with fitness-enhancing mutations at other genomic sites rather than to direct drug selection pressure. This implies that adamantanes may not be useful for treatment and prophylaxis against influenza viruses in the long term. More generally, these findings illustrate that drug selection pressure is not the sole factor determining the evolution and maintenance of drug resistance in human pathogens.",
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Simonsen, L, Viboud, C, Grenfell, BT, Dushoff, J, Jennings, L, Smit, M, Macken, C, Hata, M, Gog, J, Miller, M & Holmes, EC 2007, 'The genesis and spread of reassortment human influenza A/H3N2 viruses conferring adamantane resistance', Molecular Biology and Evolution, bind 24, nr. 8, s. 1811-1820.

The genesis and spread of reassortment human influenza A/H3N2 viruses conferring adamantane resistance. / Simonsen, Lone; Viboud, Cecile; Grenfell, Bryan T.; Dushoff, Jonathan; Jennings, Lance; Smit, Marita; Macken, Catherine; Hata, Mami; Gog, Julia; Miller, Mark; Holmes, Edward C.

I: Molecular Biology and Evolution, Bind 24, Nr. 8, 2007, s. 1811-1820.

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

TY - JOUR

T1 - The genesis and spread of reassortment human influenza A/H3N2 viruses conferring adamantane resistance

AU - Simonsen, Lone

AU - Viboud, Cecile

AU - Grenfell, Bryan T.

AU - Dushoff, Jonathan

AU - Jennings, Lance

AU - Smit, Marita

AU - Macken, Catherine

AU - Hata, Mami

AU - Gog, Julia

AU - Miller, Mark

AU - Holmes, Edward C.

PY - 2007

Y1 - 2007

N2 - A dramatic rise in the frequency of resistance to adamantane drugs by influenza A (H3N2) viruses has occurred in recent years -- from approximately 2% to approximately 90% in multiple countries worldwide-and associated with a single S31N amino acid replacement in the viral matrix M2 protein. To explore the emergence and spread of these adamantane resistant viruses we performed a phylogenetic analysis of recently sampled complete A/H3N2 genome sequences. Strikingly, all adamantane resistant viruses belonged to a single lineage (the "N-lineage") characterized by 17 amino acid replacements across the viral genome. Further, our analysis revealed that the genesis of the N-lineage was due to a 4+4 segment reassortment event involving 2 distinct lineages of influenza A/H3N2 virus. A subsequent study of hemagglutinin HA1 sequences suggested that the N-lineage was circulating widely in Asia during 2005, and then dominated the Northern hemisphere 2005-2006 season in Japan and the USA. Given the infrequent use of adamantane drugs in many countries, as well as the decades of use in the US associated with little drug resistance, we propose that the globally increasing frequency of adamantane resistance is more likely attributable to its interaction with fitness-enhancing mutations at other genomic sites rather than to direct drug selection pressure. This implies that adamantanes may not be useful for treatment and prophylaxis against influenza viruses in the long term. More generally, these findings illustrate that drug selection pressure is not the sole factor determining the evolution and maintenance of drug resistance in human pathogens.

AB - A dramatic rise in the frequency of resistance to adamantane drugs by influenza A (H3N2) viruses has occurred in recent years -- from approximately 2% to approximately 90% in multiple countries worldwide-and associated with a single S31N amino acid replacement in the viral matrix M2 protein. To explore the emergence and spread of these adamantane resistant viruses we performed a phylogenetic analysis of recently sampled complete A/H3N2 genome sequences. Strikingly, all adamantane resistant viruses belonged to a single lineage (the "N-lineage") characterized by 17 amino acid replacements across the viral genome. Further, our analysis revealed that the genesis of the N-lineage was due to a 4+4 segment reassortment event involving 2 distinct lineages of influenza A/H3N2 virus. A subsequent study of hemagglutinin HA1 sequences suggested that the N-lineage was circulating widely in Asia during 2005, and then dominated the Northern hemisphere 2005-2006 season in Japan and the USA. Given the infrequent use of adamantane drugs in many countries, as well as the decades of use in the US associated with little drug resistance, we propose that the globally increasing frequency of adamantane resistance is more likely attributable to its interaction with fitness-enhancing mutations at other genomic sites rather than to direct drug selection pressure. This implies that adamantanes may not be useful for treatment and prophylaxis against influenza viruses in the long term. More generally, these findings illustrate that drug selection pressure is not the sole factor determining the evolution and maintenance of drug resistance in human pathogens.

KW - influenza virus

KW - Adamantane resistance

KW - Reassortment

KW - hitch-hiking

KW - natural selection

M3 - Journal article

VL - 24

SP - 1811

EP - 1820

JO - Molecular Biology and Evolution

JF - Molecular Biology and Evolution

SN - 0737-4038

IS - 8

ER -