%0 Journal Article %A Hu, Meng %A Yuan, Shuofeng %A Ye, Zi-Wei %A Singh, Kailash %A Li, Cun %A Shuai, Huiping %A Fai, Ng %A Chow, Billy K. C %A Chu, Hin %A Zheng, Bo-Jian %T PAN substitutions A37S, A37S/I61T and A37S/V63I attenuate the replication of H7N7 influenza A virus by impairing the polymerase and endonuclease activities %D 2017 %J Journal of General Virology, %V 98 %N 3 %P 364-373 %@ 1465-2099 %R https://doi.org/10.1099/jgv.0.000717 %K PAN-A37S/V63I %K endonuclease activity %K influenza A virus %K PAN-A37S %K PAN-A37S/I61T %K polymerase activity %I Microbiology Society, %X Substitutions in the PA N-terminus (PAN) of influenza A viruses are associated with viral pathogenicity. During our previous study, which identified PAN-V63I and -A37S/I61T/V63I/V100A substitutions as virulence determinants, we observed a severe decrease in virus growth and transcription/replication capacity posed by PAN-A37S/V100A substitution. To further delineate the significance of substitutions at these positions, we generated mutant H7N7 viruses bearing the substitutions PAN-A37S, -A37S/I61T, -A37S/V63I, -V100A, -I61T/V100A and -V63I/V100A by reverse genetics. Our results showed that all mutant viruses except PAN-V100A showed a significantly reduced growth capability in infected cells. At the same time, the PAN-A37S, -A37S/I61T and -A37S/V63I mutant viruses displayed decreased viral transcription and replication by diminishing virus RNA synthesis activity. Biochemical assays indicated that the substitutions PAN-A37S, -A37S/I61T and -A37S/V63I suppressed the polymerase and endonuclease activities when compared with those of the wild-type. Together, our results demonstrated that the PAN-A37S, -A37S/I61T and -A37S/V63I substitutions contributed to a decreased pathogenicity of avian H7N7 influenza A virus. %U https://www.microbiologyresearch.org/content/journal/jgv/10.1099/jgv.0.000717