- 作者: Ruey-Wen Lin, Guang-Wu Chen, Hsiang-Hsuan Sung, Ren-Jye Lin, Li-Chen Yen, Yu-Ling Tseng, Yung-Kun Chang, Shu-Pei Lien, Shin-Ru Shih and Ching-Len Liao
- 作者服務機構: 1. Graduate Institute of Life Sciences, National Defense Medical Center, No. 161 Section 6, Minquan E. Road, Taipei, 114, Taiwan 2. Research Center for Emerging Viral Infections, College of Medicine, Chang Gung University, No. 259, Wen Hwa 1st Road, Kwei-Shan, Taoyuan, 333, Taiwan 3. Department of Laboratory Medicine, Linkou Chang Gung Memorial Hospital, No. 5 Fu Hsing Street, Kwei-Shan, Taoyuan, 333, Taiwan 4. Department of Computer Science and Information Engineering, School of Electrical and Computer Engineering, College of Engineering, Chang Gung University, No. 259, Wen Hwa 1st Road, Kwei-Shan, Taoyuan, 333, Taiwan 5. National Laboratory Animal Center, Nation Applied Research Laboratory, No.106, Sec. 2, Heping E. Rd., Taipei, 10622, Taiwan 6. National Mosquito-Borne Diseases Control Research Center, National Health Research Institute, 10 F, Bldg F, 3 Yuanqu Street, Taipei, 11503, Taiwan
- 中文摘要:
- 英文摘要:
Background
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.
Methods
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.
Results
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.
Conclusions
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. - 中文關鍵字:
- 英文關鍵字: Influenza A/H1N1, PB1, RdRp, Fidelity, Fitness, Neuraminidase