ABED Y, GOYETTE N, BOIVIN G; Interscience Conference on Antimicrobial Agents and Chemotherapy (43rd: 2003: Chicago, Ill.).

Abstr Intersci Conf Antimicrob Agents Chemother Intersci Conf Antimicrob Agents Chemother. 2003 Sep 14-17; 43: abstract no. V-481.

CHUQ-CHUL, Laval University, Quebec, PQ, Canada.

BACKGROUND: In influenza A viruses, resistance to neuraminidase inhibitors (NIs) results from mutations in the neuraminidase (NA) and/or the hemagglutinin (HA) genes whereas resistance to amantadine (AMT) is conferred by mutations in the M2 gene. The aim of this study was to generate and characterize viral recombinants with NA and M2 mutations previously associated with resistance to NIs and AMT in clinical isolates. METHODS: Reverse genetics was used to generate recombinant NA and M2 mutants from the influenza A/WSN/33 (H1N1) virus. NA inhibition tests and plaque reduction assays (PRA) were used to determine the susceptibility of wild-type (WT) and NA mutants to Zanamivir (ZMV), Oseltamivir (OSV) and BCX-1812 whereas M2 mutants susceptibility to AMT was evaluated by PRA. RESULTS: 1. The recombinant H274Y NA mutant was generated whereas the R292K and E119G mutants (previously reported in NI-resistant H3N2 and H1N9 viruses) could not be rescued. In NA inhibition tests, the H274Y showed a high level of resistance to OSV (440 X) and BCX-1812 (50 X) compared to the WT while ZMV IC50 value was unaltered. Similar suceptibility profiles were obtained in PRA. The plaque size of the mutant was significantly smaller than that of WT. 2. Three single (A27T, S31N, and G34E) and 2 double (A27T+S31N and S31N+G34E) M2 mutants were rescued. The AMT IC50 values of single mutants increased by 260- to 3000- fold compared to that of the WT. Interestingly, the double (A27T+S31N) mutant was less resistant than each of the single mutant viruses. The WT and M2 mutants generated plaques of a similar size. CONCLUSIONS: 1. The NA resistance mutations may occur in a subtype specific manner. 2. M2 mutations may be associated with different levels of resistance to AMT without a synergistic effect. 3. Based on viral plaque size, the viral fitness seemed to be affected by NA but not by M2 mutations.

Publication Types:

• Meeting Abstracts

Keywords:

• Acetamides
• Amantadine
• Antiviral Agents
• Cyclopentanes
• Hemagglutinins
• Influenza A virus
• Mutation
• Neuraminidase
• Oseltamivir
• Plaque Assay
• Sialic Acids
• Zanamivir
• genetics
• peramivir

Other ID:

• GWAIDS0025556

UI: 102265180

From Meeting Abstracts