Temperature-Sensitive Mutants of Influenza A Virus: Production and Characterization of A/Victoria/3/75-ts-1[E] Recombinants

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The Hong Kong/68-ts-1[E] virus, which has a 38°C shutoff temperature for plaque formation, has been proposed as a donor of its two ts lesions to new variants of influenza A virus that pose an epidemic threat. To further examine whether the acquisition of the two ts-1[E] lesions will predictably attenuate new influenza A variants, the HK/68-ts-1[E] virus was mated with the A/Vic/3/75 wild-type virus. The Vic/75-ts-[E] recombinants that had the two ts-1[E] lesions also had a 38°C shutoff temperature. Two Vic/75-ts-1[E] recombinants (clones 81 and 113) that had the two ts-1[E] lesions, a 38°C shutoff temperature, and the Vic/75 hemagglutinin and neuraminidase glycoproteins were similar to each other and to their ts-1[E] parent in the pattern of replication and genetic stability in hamsters. These findings support the hypothesis that the acquisition of the two ts-1[E] lesions will predictably attenuate wild-type influenza A virus. Each Vic/75-ts-1[E] recombinant virus that possessed only the group 1 ts-1[E] lesion had a 39°C shutoff temperature. Two of three of the Vic/75-ts-1[E] recombinants that had only the group 2 ts-1[E] lesion had a 39°C shutoff temperature. This suggests that the HK/68-ts-1[E] donor virus contains two ts genes each of which by itself restricts plaque formation at 39°C and above. The HK/68-ts-1[E] parent virus and its Vic/75 recombinant clones 81 and 113 were evaluated in ferret tracheal organ cultures maintained at permissive and restrictive temperatures. The Vic/75-ts-1[E] clone 81 differed from its parent and sister clone 113 in that it replicated readily and caused ciliostasis at 37°C, a temperature restrictive for the replication of other ts-1[E] recombinants with a 38°C shutoff temperature. The genetic basis underlying this difference was not elucidated.

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