Naturally occurring mutations in PB1 affect influenza A virus replication fidelity, virulence, and adaptability

• Published in: Journal of biomedical science Vol. 26; no. 1; p. 55
• Main Authors: Lin, Ruey-Wen, Chen, Guang-Wu, Sung, Hsiang-Hsuan, Lin, Ren-Jye, Yen, Li-Chen, Tseng, Yu-Ling, Chang, Yung-Kun, Lien, Shu-Pei, Shih, Shin-Ru, Liao, Ching-Len
• Format: Journal Article
• Language: English
• Published: England BioMed Central Ltd 31.07.2019; BioMed Central; BMC
• Subjects: Adaptation, Physiological - genetics; Algorithms; Amino acids; Animals; Dogs; Epidemics; Epidemiology; Fidelity; Fitness; Genetic aspects; Glycine; HEK293 Cells; Humans; Influenza; Influenza A virus - genetics; Influenza A virus - physiology; Influenza A/H1N1; Influenza viruses; Madin Darby Canine Kidney Cells; Microbiological research; Mutation; Mutation - genetics; Neuraminidase; Oseltamivir phosphate; PB1; RdRp; Ribavirin; RNA; Serine; Swine; Viral Proteins - genetics; Viral Proteins - metabolism; Virulence (Microbiology); Virulence - genetics; Virus replication; Virus Replication - genetics; Taiwan; Fidelity; RdRp; PB1; Influenza A/H1N1; Neuraminidase; Fitness
• ISSN: 1423-0127; 1021-7770; 1423-0127
• DOI: 10.1186/s12929-019-0547-4

Mutations in the PB1 subunit of RNA-dependent RNA polymerase (RdRp) of influenza A virus can affect replication fidelity. Before the influenza A/H1N1 pandemic in 2009, most human influenza A/H1N1 viruses contained the avian-associated residue, serine, at position 216 in PB1. However, near the onset of the 2009 pandemic, human viruses began to acquire the mammalian-associated residue, glycine, at PB1-216, and PB1-216G became predominant in human viruses thereafter. Using entropy-based analysis algorithm, we have previously identified several host-specific amino-acid signatures that separated avian and swine viruses from human influenza viruses. The presence of these host-specific signatures in human influenza A/H1N1 viruses suggested that these mutations were the result of adaptive genetic evolution that enabled these influenza viruses to circumvent host barriers, which resulted in cross-species transmission. We investigated the biological impact of this natural avian-to-mammalian signature substitution at PB1-216 in human influenza A/H1N1 viruses. We found that PB1-216G viruses had greater mutation potential, and were more sensitive to ribavirin than PB1-216S viruses. In oseltamivir-treated HEK293 cells, PB1-216G viruses generated mutations in viral neuraminidase at a higher rate than PB1-216S viruses. By contrast, PB1-216S viruses were more virulent in mice than PB1-216G viruses. These results suggest that the PB1-S216G substitution enhances viral epidemiological fitness by increasing the frequency of adaptive mutations in human influenza A/H1N1 viruses. Our results thus suggest that the increased adaptability and epidemiological fitness of naturally arising human PB1-216G viruses, which have a canonical low-fidelity replicase, were the biological mechanisms underlying the replacement of PB1-216S viruses with a high-fidelity replicase following the emergence of pdmH1N1. We think that continued surveillance of such naturally occurring PB1-216 variants among others is warranted to assess the potential impact of changes in RdRp fidelity on the adaptability and epidemiological fitness of human A/H1N1 influenza viruses.