RT Journal Article SR Electronic(1) A1 Li, Jing A1 Li, Yongqiang A1 Hu, Yi A1 Chang, Guohui A1 Sun, Wei A1 Yang, Yinhui A1 Kang, Xiaoping A1 Wu, Xiaoyan A1 Zhu, QingyuYR 2011 T1 PB1-mediated virulence attenuation of H5N1 influenza virus in mice is associated with PB2 JF Journal of General Virology, VO 92 IS 6 SP 1435 OP 1444 DO https://doi.org/10.1099/vir.0.030718-0 PB Microbiology Society, SN 1465-2099, AB H5N1 avian influenza viruses demonstrate different phenotypes, such as pathogenicity after one or serial passages in mammalian hosts or cells. To establish the molecular basis of these phenotypes, we cloned isolates from the lungs of mice infected with human A/Vietnam/1194/2004 (H5N1) influenza virus. Large-plaque isolates were less pathogenic to mice than small-plaque isolates. Genome sequencing revealed that the small-plaque and large-plaque isolates differed in several amino acids. In order to assess their effects on pathogenicity in mice, two amino acid changes common to attenuated isolates, one in PB2 (I63T) and the other in PB1 (T677M), were inserted into a wild-type recombinant virus construct. The PB2 (I63T) or PB1 (T677M) mutations alone did not alter the phenotype of H5N1 virus, whereas recombinant virus with both mutations was less pathogenic than the wild-type recombinant virus. Furthermore, the PB1 (T677M) mutation showed a lower replication efficiency, although it had higher polymerase activity. The recombinant virus with the PB2 (63T) mutation replicated as well as the wild-type recombinant virus. These results suggest that the C terminus of PB1 of H5N1 influenza virus mediates virulence attenuation of H5N1 influenza virus in mice, associating with the N terminus of PB2. However, the role of the N terminus of PB2 in virulence attenuation in mice remains unclear., UL https://www.microbiologyresearch.org/content/journal/jgv/10.1099/vir.0.030718-0