tetano
Editor, Senior Moderator
J Biomed Sci. 2019 Jul 31;26(1):55. doi: 10.1186/s12929-019-0547-4.
[h=1]Naturally occurring mutations in PB1 affect influenza A virus replication fidelity, virulence, and adaptability.[/h] Lin RW[SUP]1[/SUP], Chen GW[SUP]2,[/SUP][SUP]3,[/SUP][SUP]4[/SUP], Sung HH[SUP]5[/SUP], Lin RJ[SUP]6[/SUP], Yen LC[SUP]7[/SUP], Tseng YL[SUP]7[/SUP], Chang YK[SUP]7[/SUP], Lien SP[SUP]8[/SUP], Shih SR[SUP]2,[/SUP][SUP]3,[/SUP][SUP]9[/SUP], Liao CL[SUP]10,[/SUP][SUP]11,[/SUP][SUP]12,[/SUP][SUP]13[/SUP].
[h=3]Author information[/h]
[h=3]Abstract[/h] [h=4]BACKGROUND:[/h] 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.
[h=4]METHODS:[/h] 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.
[h=4]RESULTS:[/h] 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.
[h=4]CONCLUSIONS:[/h] 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.
[h=4]KEYWORDS:[/h] Fidelity; Fitness; Influenza A/H1N1; Neuraminidase; PB1; RdRp
PMID: 31366399 DOI: 10.1186/s12929-019-0547-4
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[h=1]Naturally occurring mutations in PB1 affect influenza A virus replication fidelity, virulence, and adaptability.[/h] Lin RW[SUP]1[/SUP], Chen GW[SUP]2,[/SUP][SUP]3,[/SUP][SUP]4[/SUP], Sung HH[SUP]5[/SUP], Lin RJ[SUP]6[/SUP], Yen LC[SUP]7[/SUP], Tseng YL[SUP]7[/SUP], Chang YK[SUP]7[/SUP], Lien SP[SUP]8[/SUP], Shih SR[SUP]2,[/SUP][SUP]3,[/SUP][SUP]9[/SUP], Liao CL[SUP]10,[/SUP][SUP]11,[/SUP][SUP]12,[/SUP][SUP]13[/SUP].
[h=3]Author information[/h]
[h=3]Abstract[/h] [h=4]BACKGROUND:[/h] 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.
[h=4]METHODS:[/h] 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.
[h=4]RESULTS:[/h] 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.
[h=4]CONCLUSIONS:[/h] 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.
[h=4]KEYWORDS:[/h] Fidelity; Fitness; Influenza A/H1N1; Neuraminidase; PB1; RdRp
PMID: 31366399 DOI: 10.1186/s12929-019-0547-4
Free full text