Commentary
Coincident Tamiflu and Relenza Resistance Sequences in NJ
Recombinomics Commentary 12:36
August 15, 2008
The recently released H1N1 sequences from South Africa confirm earlier reports indicating Tamiflu (oseltamivir) resistance had increased to 100% (23 of the first 23 isolates had H274Y). The released 8 NA sequences all had H274Y while the 8 HA sequences mapped with other HA sequences from isolates with H274Y.
Five of the HA sequences had a cluster of 5 polymorphisms, indicating they were rapidly evolving away from the oseltamivir resistant Brisbane/59 HA sequence via homologous recombination. Phylogenetic analysis of other HA sequences on the same branch indicated published NA sequences had H274Y. Most of these sequences were from New Jersey (see list below). However, one of the isolates, A/New Jesey/08/2008, did not have H274Y (Tamiflu resistance), but did have a mixed signal for Q136R, which likely caused zinamivir (Relenza) resistance. Isolates with Q136K have been reported to be Relenza resistance, so changing the acidic Q at position 136 to either basic amino acids (K or R) will likely cause Relenza resistance.
The Relenza and Tamiflu resistance coincident with similar HA sequences raises concern that these polymorphisms create a selective advantage for H1N1 in the absence of either neuraminidase inhibitor. If true, the increasing level of the HA sequence associated with Tamiflu resistance may lead to an increase in Relenza resistance, regardless of Tamiflu or Relenza usage.
The New Jersey sequences fro HA and NA are mixtures, so resequencing of plaque purified clones would be useful. Similarly, full sequencing of all eight gene segments may help taget changes that lead to selection of additional changes which confir resistance to the nuraminidase inhibitors, oseltamivir (Tamiflu) and zinamivir (Relenza).
HA Sequences Mapping With New Jersey/08/2008
Hawaii/02/2008
Johannesburg/10/2008
Johannesburg/25/2008
Johannesburg/34/2008
Johannesburg/35/2008
Johannesburg/46/2008
Maryland/04/2007
Memphis/03/2008
New Jersey/15/2007
New Jersey/16/2007
New Jersey/20/2007
New Jersey/05/2008
New Jersey/06/2008
New Jersey/10/2008
North Carolina/02/2008
Pennsylvania/02/2008
South Carolina/01/2008
Washington/01/2008
Wisconsin/01/2008
Media Links
Recombinomics Presentations
Recombinomics Publications
Recombinomics Paper at Nature Precedings