Attenuation of wild-type human influenza A virus by acquisition of the PA polymerase and matrix protein genes of influenza A/Ann Arbor/6/60 cold-adapted donor virus.
Wild-type influenza A viruses can be attenuated for humans by the acquisition of genes from the A/Ann Arbor/6/60 cold-adapted (ca) donor virus. Six-gene reassortants, that is, viruses containing the hemagglutinin and neuraminidase surface glycoprotein genes of the wild-type virus and the six remaining RNA segments of the ca donor virus, are consistently attenuated for humans. During the production of a six-gene reassortant virus containing the surface glycoproteins of the A/Washington/897/80 (H3N2) wild-type virus, a reassortant virus was isolated that contained RNA segments 3 (coding for the polymerase PA protein) and 7 (coding for matrix [M] proteins) from the ca parent and all other genes from the wild-type virus. This reassortant virus is referred to as a two-gene reassortant. Because the gene or set of genes responsible for the attenuation of ca reassortant viruses has not been defined, we evaluated the two-gene reassortant for level of replication and level of virulence in ferrets and in humans, and we compared its characteristics to those of a six-gene reassortant virus derived from the same two parents. The two-gene reassortant virus infected each of 14 adult seronegative (serum hemagglutination inhibition titer of less than or equal to 1:8) volunteers when administered intranasally at a dose of 10(7) 50% tissue culture infectious doses, yet it did not produce illness. The level of replication of the two-gene reassortant virus in the upper respiratory tract was equivalent to that of the six-gene reassortant virus. This demonstrates that transfer of the A/Ann Arbor/6/60 ca PA polymerase and M genes is sufficient to confer the attenuation phenotype on wild-type influenza A viruses. In the context of previous observations, these results suggest that the A/Ann Arbor/6/60 ca donor virus PA polymerase gene plays a major role in the attenuation of ca reassortant viruses.
D000818:Animals; D012321:DNA-Directed RNA Polymerases / Q000235:genetics* / Q000276:immunology; D005289:Ferrets / Q000382:microbiology; D005814:Genes, Viral; D005838:Genotype; D006801:Humans; D009980:Influenza A virus / Q000235:genetics / Q000472:pathogenicity*; D011995:Recombination, Genetic; D013696:Temperature; D014613:Vaccines, Attenuated / Q000276:immunology; D014763:Viral Matrix Proteins; D010948:Viral Plaque Assay; D014764:Viral Proteins / Q000235:genetics* / Q000276:immunology; D014765:Viral Vaccines / Q000276:immunology*; D014779:Virus Replication
D014613:Vaccines, Attenuated; D014763:Viral Matrix Proteins; D014764:Viral Proteins; D014765:Viral Vaccines; D012321:DNA-Directed RNA Polymerases