tetano
Editor, Senior Moderator
Emerg Microbes Infect. 2014 Nov;3(11):e78. doi: 10.1038/emi.2014.80. Epub 2014 Nov 12.
[h=1]Drug susceptibility profile and pathogenicity of H7N9 influenza virus (Anhui1 lineage) with R292K substitution.[/h] Zhang X[SUP]1[/SUP], Song Z[SUP]1[/SUP], He J[SUP]1[/SUP], Yen HL[SUP]2[/SUP], Li J[SUP]3[/SUP], Zhu Z[SUP]1[/SUP], Tian D[SUP]1[/SUP], Wang W[SUP]1[/SUP], Xu L[SUP]1[/SUP], Guan W[SUP]1[/SUP], Liu Y[SUP]1[/SUP], Wang S[SUP]4[/SUP], Shi B[SUP]1[/SUP], Zhang W[SUP]1[/SUP], Qin B[SUP]5[/SUP], Cai J[SUP]5[/SUP], Wan Y[SUP]6[/SUP], Xu C[SUP]5[/SUP], Ren X[SUP]5[/SUP], Chen H[SUP]1[/SUP], Liu L[SUP]6[/SUP], Yang Y[SUP]5[/SUP], Zhou X[SUP]5[/SUP], Zhou W[SUP]5[/SUP], Xu J[SUP]7[/SUP], Zhang X[SUP]7[/SUP], Peiris M[SUP]2[/SUP], Hu Y[SUP]1[/SUP], Yuan Z[SUP]3[/SUP].
[h=3]Author information[/h]
[h=3]Abstract[/h] Neuraminidase inhibitors (NAIs) are the only available licensed therapeutics against human H7N9 influenza virus infections. The emergence of NAI-resistant variants of H7N9viruses with an NA R292K mutation poses a therapeutic challenge. A comprehensive understanding of the susceptibility of these viruses to clinically available NAIs, non-NAIs and their combinations is crucial for effective treatment. In this study, by using limited serial passage and plaque purification, an R292K variant of the Anhui1 lineage was isolated from a patient with clinical evidence of resistance to oseltamivir. In vitro and cell-based assays confirmed a high level of resistance conferred by the R292K mutation to oseltamivir carboxylate and a moderate level of resistance to zanamivir and peramivir. Non-NAI antivirals, such as T-705, ribavirin and NT-300, efficiently inhibited both the variant and the wild-type in cell-based assays. A combination of NAIs and non-NAIs did not exhibit a marked synergistic effect against the R292K variant. However, the combination of two non-NAIs (T-705 and ribavirin) exhibited significant synergism against the mutant virus. In experimentally infected mice, the variant showed delayed onset of symptoms, a reduced viral load and attenuated lethality compared with the wild-type. Our study suggested non-NAIs should be tested clinically for H7N9 patients with a sustained high viral load. Possible drug combination regimens, such as T-705 plus ribavirin, should be further tested in animal models. The pathogenicity and transmissibility of the R292K H7N9 variant should be further assessed with genetically well-characterized pairs of viruses and, most-desirably, with competitive fitness experiments.
[h=4]KEYWORDS:[/h] H7N9; influenza virus; neuraminidase; oseltamivir; peramivir
PMID: 26038501 [PubMed] PMCID: PMC4274890 Free PMC Article
[h=1]Drug susceptibility profile and pathogenicity of H7N9 influenza virus (Anhui1 lineage) with R292K substitution.[/h] Zhang X[SUP]1[/SUP], Song Z[SUP]1[/SUP], He J[SUP]1[/SUP], Yen HL[SUP]2[/SUP], Li J[SUP]3[/SUP], Zhu Z[SUP]1[/SUP], Tian D[SUP]1[/SUP], Wang W[SUP]1[/SUP], Xu L[SUP]1[/SUP], Guan W[SUP]1[/SUP], Liu Y[SUP]1[/SUP], Wang S[SUP]4[/SUP], Shi B[SUP]1[/SUP], Zhang W[SUP]1[/SUP], Qin B[SUP]5[/SUP], Cai J[SUP]5[/SUP], Wan Y[SUP]6[/SUP], Xu C[SUP]5[/SUP], Ren X[SUP]5[/SUP], Chen H[SUP]1[/SUP], Liu L[SUP]6[/SUP], Yang Y[SUP]5[/SUP], Zhou X[SUP]5[/SUP], Zhou W[SUP]5[/SUP], Xu J[SUP]7[/SUP], Zhang X[SUP]7[/SUP], Peiris M[SUP]2[/SUP], Hu Y[SUP]1[/SUP], Yuan Z[SUP]3[/SUP].
[h=3]Author information[/h]
[h=3]Abstract[/h] Neuraminidase inhibitors (NAIs) are the only available licensed therapeutics against human H7N9 influenza virus infections. The emergence of NAI-resistant variants of H7N9viruses with an NA R292K mutation poses a therapeutic challenge. A comprehensive understanding of the susceptibility of these viruses to clinically available NAIs, non-NAIs and their combinations is crucial for effective treatment. In this study, by using limited serial passage and plaque purification, an R292K variant of the Anhui1 lineage was isolated from a patient with clinical evidence of resistance to oseltamivir. In vitro and cell-based assays confirmed a high level of resistance conferred by the R292K mutation to oseltamivir carboxylate and a moderate level of resistance to zanamivir and peramivir. Non-NAI antivirals, such as T-705, ribavirin and NT-300, efficiently inhibited both the variant and the wild-type in cell-based assays. A combination of NAIs and non-NAIs did not exhibit a marked synergistic effect against the R292K variant. However, the combination of two non-NAIs (T-705 and ribavirin) exhibited significant synergism against the mutant virus. In experimentally infected mice, the variant showed delayed onset of symptoms, a reduced viral load and attenuated lethality compared with the wild-type. Our study suggested non-NAIs should be tested clinically for H7N9 patients with a sustained high viral load. Possible drug combination regimens, such as T-705 plus ribavirin, should be further tested in animal models. The pathogenicity and transmissibility of the R292K H7N9 variant should be further assessed with genetically well-characterized pairs of viruses and, most-desirably, with competitive fitness experiments.
[h=4]KEYWORDS:[/h] H7N9; influenza virus; neuraminidase; oseltamivir; peramivir
PMID: 26038501 [PubMed] PMCID: PMC4274890 Free PMC Article