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N294S Tamiflu Resistance is Evolutionarily Fit
Recombinomics Commentary
January 18, 2007

“Given the information we have, we don’t see any broad public health implications,” said Dick Thompson, a spokesman for the organization.
Mr. Thompson was unsure which Egyptian cluster of flu infections the patients were part of. But another source said it was one in Gharbiya Province, roughly 50 miles north of Cairo, in which flu killed three people last month in a 33-member family living in one compound.

Oseltamivir-resistant strains were found in three unrelated patients in Vietnam in 2005 but did not spread.

The above comments on Tamiflu resistance in H5N1 are incomplete.  Previously, H274Y has been found in H5N1 patients that have been treated with Tamiflu.  However, this change appears to have developed during treatment.  It was not detected in initial collections from the patient, or was initially present at low levels.  This change is the only prior reported H5N1 oseltamivir resistant change in H5N1 in patients.  However, data in the literature on H274Y indicates this change is not evolutionarily fit, and therefore H5N1 with this change has not been islated from sources other than patients undergoing Tamiflu treatment.

However, N294S has been detected previously in H5N1 in ducks in China (A/duck/Zhejiang/bj/2002(H5N1) and A/Duck/Hong Kong/380.5/2001(H5N1)).  Both of these isolates were highly pathogenic with the common HA cleavage site, RERRRKKR), but did not have the 20 amino acid deletion, which defines the Z genotype, including the Qinghai strain that is transmitted and transported by migratory birds, including the teal identified in Egypt in December, 2005.

However, N294S has not been previously reported in patients or the Qinghai strain of H5N1.  Most of the NA Qinghai sequences have been sequestered in the private WHO database at Los Alamos.  This private database is used by Weybridge, who has sequenced a large number of Qinghai isolates in Europe and the Middle East, as well as the CDC in Atlanta, which gets samples from NAMRU-3 in Cairo.  Thus, N294S may have already been identified in Qinghai H5N1, but that information is not public.

The presence of N294S in H5N1 in ducks in China however, creates a source for the acquisition of the change via recombination.  The presence of N294S in both patients in samples collected within 48 hours of Tamiflu treatment suggests the sequences were present prior to Tamiflu treatment of the three cluster members.  All three failed to respond to treatment and died.

More NA sequence data on additional patients and birds in Egypt would be useful.

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