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Edward Holmes is no dummy. He detected a pattern that would be repeated in subsequent years for other antiviral agents.
<b>The Genesis and Spread of Reassortant Human Influenza A/H3N2 Viruses Conferring Adamantane Resistance.</b> Lone Simonsen, C?cile Viboud, Bryan T. Grenfell, Jonathan Dushoff,?, Lance Jennings, Marita Smit, Catherine Macken, Mami Hata, Julia Gog, Mark A Miller and Edward C. Holmes. Molecular Biology and Evolution 2007 24(8):1811-1820. Accepted for publication May 15, 2007.
A dramatic rise in the frequency of resistance to adamantane drugs by influenza A (H3N2) viruses has occurred in recent years ? from ~2% to ~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 two 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.
<i>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.</i>
Advanced Access Manuscript:
http://mbe.oxfordjournals.org/cgi/reprint/msm103v1
From the Discussion:
Our phylogenetic analysis of influenza A/H3N2 virus genome sequence data reveals the existence of a distinct lineage (N-lineage) of predominantly adamantane resistant viruses at high frequency in many locations globally. As adamantane drugs have rarely been used in countries like New Zealand and Japan in recent years, and used in the US for decades (at constant or recently declining rates) with extremely low levels of drug resistance, it is unlikely that local drug selection pressure is directly responsible for the recent spread and maintenance of the N-lineage in these countries.
Indeed, the N-lineage also contains a small subset of viruses that do not possess the S31N mutation and, importantly, none of the other mutations associated with adamantane resistance were observed in our data set. We therefore propose that the rapid spread of adamantane resistance is due to its interaction with other genomic mutations, most likely through hitch-hiking with advantageous mutations located elsewhere in the viral genome, although the possibility of selectively mediated epistatic interactions cannot be excluded.
This hypothesis is further supported by the observation that adamantane resistant mutants have similar fitness to wild-type viruses in animal passage experiments, so that resistant viruses may revert slowly, if at all, in the absence of adamantane selection pressure (Bean et al. 1989). Also, we note that there is no correlation between the geographical distribution of adamantane resistance in influenza A/H5N1 viruses infecting poultry in the Far East and local drug-use prevalence (Cheung et al. 2006), again countering the drug selection theory. However, it will be necessary to undertake experimental tests of the phenotypic consequences of the 17 amino acid substitutions that characterize the N-lineage.
Our genome-wide phylogenetic analysis also reveals that a 4+4 reassortment event involving two phylogenetically distinct lineages of A/H3N2 influenza virus was responsible for the genesis of the N-lineage. Although multiple reassortment events have previously been observed in influenza A virus evolution (Lindstrom et al. 2004), we believe that this is the first time that such a 4+4 segment reassortment event has been reported. Hence, our study further demonstrates the potential for reassortment to profoundly effect patterns of genetic diversity, and hence the fitness, of influenza viruses. However, whether the patterns of segment evolution observed reflect functional compatibilities, or merely chance associations, is unknown and clearly merits additional study.
Further, that viruses of phylogenetic pattern B were evidently at low frequency during 2003-2005, yet continuing to accumulate nucleotide substitutions, suggests that a more intensive global survey of viral genetic diversity may uncover additional distinct lineages of A/H3N2, including those that exhibit important phenotypic differences such as drug resistance.
<b>The Genesis and Spread of Reassortant Human Influenza A/H3N2 Viruses Conferring Adamantane Resistance.</b> Lone Simonsen, C?cile Viboud, Bryan T. Grenfell, Jonathan Dushoff,?, Lance Jennings, Marita Smit, Catherine Macken, Mami Hata, Julia Gog, Mark A Miller and Edward C. Holmes. Molecular Biology and Evolution 2007 24(8):1811-1820. Accepted for publication May 15, 2007.
A dramatic rise in the frequency of resistance to adamantane drugs by influenza A (H3N2) viruses has occurred in recent years ? from ~2% to ~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 two 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.
<i>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.</i>
Advanced Access Manuscript:
http://mbe.oxfordjournals.org/cgi/reprint/msm103v1
From the Discussion:
Our phylogenetic analysis of influenza A/H3N2 virus genome sequence data reveals the existence of a distinct lineage (N-lineage) of predominantly adamantane resistant viruses at high frequency in many locations globally. As adamantane drugs have rarely been used in countries like New Zealand and Japan in recent years, and used in the US for decades (at constant or recently declining rates) with extremely low levels of drug resistance, it is unlikely that local drug selection pressure is directly responsible for the recent spread and maintenance of the N-lineage in these countries.
Indeed, the N-lineage also contains a small subset of viruses that do not possess the S31N mutation and, importantly, none of the other mutations associated with adamantane resistance were observed in our data set. We therefore propose that the rapid spread of adamantane resistance is due to its interaction with other genomic mutations, most likely through hitch-hiking with advantageous mutations located elsewhere in the viral genome, although the possibility of selectively mediated epistatic interactions cannot be excluded.
This hypothesis is further supported by the observation that adamantane resistant mutants have similar fitness to wild-type viruses in animal passage experiments, so that resistant viruses may revert slowly, if at all, in the absence of adamantane selection pressure (Bean et al. 1989). Also, we note that there is no correlation between the geographical distribution of adamantane resistance in influenza A/H5N1 viruses infecting poultry in the Far East and local drug-use prevalence (Cheung et al. 2006), again countering the drug selection theory. However, it will be necessary to undertake experimental tests of the phenotypic consequences of the 17 amino acid substitutions that characterize the N-lineage.
Our genome-wide phylogenetic analysis also reveals that a 4+4 reassortment event involving two phylogenetically distinct lineages of A/H3N2 influenza virus was responsible for the genesis of the N-lineage. Although multiple reassortment events have previously been observed in influenza A virus evolution (Lindstrom et al. 2004), we believe that this is the first time that such a 4+4 segment reassortment event has been reported. Hence, our study further demonstrates the potential for reassortment to profoundly effect patterns of genetic diversity, and hence the fitness, of influenza viruses. However, whether the patterns of segment evolution observed reflect functional compatibilities, or merely chance associations, is unknown and clearly merits additional study.
Further, that viruses of phylogenetic pattern B were evidently at low frequency during 2003-2005, yet continuing to accumulate nucleotide substitutions, suggests that a more intensive global survey of viral genetic diversity may uncover additional distinct lineages of A/H3N2, including those that exhibit important phenotypic differences such as drug resistance.
