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

Abstract

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. Electronic supplementary material The online version of this article (10.1186/s12929-019-0547-4) contains supplementary material, which is available to authorized users.

Acquisition of Avian-Origin PB1 Facilitates Viral RNA Synthesis by the 2009 Pandemic H1N1 Virus Polymerase

“…In this regard, the pH1N1 virus is beneficial in not acquiring mutations that lead to an increased polymerase activity, such as acquiring the avian-origin PB1 or PB2-627K. A recent study may partially explain the benefit, as PB1 of pH1N1 carrying mammalian-associated glycine at amino acid 216 (PB1-216G) could acquire Oseltamivir-resistant mutation at a faster rate than the virus carrying an avian-associated serine (PB1-216S) [17], which allows the pH1N1 virus to escape from therapeutic treatment. However, monitoring the introduction of avian PB1 genes into the 2009 pandemic influenza viruses is warranted for the emergence of a potential influenza virus with increased pathogenicity.…”

“…It contains the PB2 and PA gene segments of avian-origin, and the PB1 segment originated from human seasonal H3N2 viruses. Although the seasonal H3N2 PB1 gene is originated from an avian virus, it is circulating in humans since 1968, and PB1 acquired some mammalian-associated mutations [17]. In a ferret model, the 2009 pH1N1 exhibited increased viral replication and pathogenicity compared to a seasonal H1N1 strain [18], whereas it showed mild to moderate virulence in mice compared to the reconstructed 1918 pandemic H1N1 and a highly pathogenic H5N1 virus [19].…”

Evidence of the Recombinant Origin and Ongoing Mutations in Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2)

“…With the global spread of SARS-CoV-2, its amino acid sequence is also significantly varied (Figure 3). Usually, RNA viruses have high rate of genetic mutations, which leads to evolution and provide them with increased adaptability (Lin et al, 2019). To further explore SARS-CoV-2 evolution in human, we have performed phylogenetic analysis based on the aforementioned SARS-CoV-2 in correspondence with their amino acid substitution.…”

Comparative Genomic and Proteomic Analysis of SARS CoV-2 - with Potential Mutation Probabilities and Drug Targeting

“…RNA viruses have a high genetic mutation rate. This property leads to evolutionary differentiation and change in their virulence properties (Lin et al, 2019). Analysis of the probabilities of evolutionary change and the mutation risks of the nucleotides and amino acids for SARS-CoV-2 indicate targets with low mutation potential in regards to studies on drug and vaccine design and ensure that the durability of the treatment to be developed is long-term.…”