H1N1 influenza viruses varying widely in hemagglutinin stability transmit efficiently from swine to swine and to ferrets

Russier, Marion; Yang, Guohua; Marinova‐Petkova, Atanaska; Vogel, Peter; Kaplan, Bryan S.; Webby, Richard J.; Russell, Charles J.

doi:10.1371/journal.ppat.1006276

Cited by 33 publications

(64 citation statements)

References 70 publications

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“…The H6 protein had a midpoint of thermal denaturation ( T m ) of 53.4 (Fig B). In comparison, the H1 HA of A/CA/04/09 has a T m of 57.9°C similar to that measured with whole human viruses and characteristic of an early 2009 pandemic human virus HA with fusion at pH 5.8 or lower (Fig C; Peacock et al , ; Russier et al , ). The H6 G225D protein had a midpoint of thermal denaturation ( T m ) of 50.5°C (Fig D), showing that the G225D mutation if anything slightly decreases stability (Linster et al , ; de Vries et al , ).…”

Section: Resultssupporting

confidence: 65%

A single mutation in Taiwanese H6N1 influenza hemagglutinin switches binding to human‐type receptors

et al. 2017

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In June 2013, the first case of human infection with an avian H6N1 virus was reported in a Taiwanese woman. Although this was a single non‐fatal case, the virus continues to circulate in Taiwanese poultry. As with any emerging avian virus that infects humans, there is concern that acquisition of human‐type receptor specificity could enable transmission in the human population. Despite mutations in the receptor‐binding pocket of the human H6N1 isolate, it has retained avian‐type (NeuAcα2‐3Gal) receptor specificity. However, we show here that a single nucleotide substitution, resulting in a change from Gly to Asp at position 225 (G225D), completely switches specificity to human‐type (NeuAcα2‐6Gal) receptors. Significantly, G225D H6 loses binding to chicken trachea epithelium and is now able to bind to human tracheal tissue. Structural analysis reveals that Asp225 directly interacts with the penultimate Gal of the human‐type receptor, stabilizing human receptor binding.

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Section: Resultssupporting

confidence: 65%

A single mutation in Taiwanese H6N1 influenza hemagglutinin switches binding to human‐type receptors

et al. 2017

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“…Further analysis of swine H1N1 viruses isolated after the 2009 pandemic revealed a shift in HA activation pH. Multiple post-2009 pandemic isolates had activation pH values that overlapped those of viruses that were adapted to humans, suggesting pigs as a bridging host for HA stabilization (64). In the current study, the lowest activation pH was observed for H1 viruses that were capable of sustained transmission in humans: Bris/59 (pH 5.3 to 5.4) and H1N1pdm09 viruses CA/07 and TX/15 (pH 5.4 to 5.5).…”

Section: Discussionmentioning

confidence: 99%

Comparative In Vitro and In Vivo Analysis of H1N1 and H1N2 Variant Influenza Viruses Isolated from Humans between 2011 and 2016

Pulit-Penaloza

Pappas

Belser

et al. 2018

J Virol

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Influenza A virus pandemics are rare events caused by novel viruses which have the ability to spread in susceptible human populations. With respect to H1 subtype viruses, swine H1N1 and H1N2 viruses occasionally cross the species barrier to cause human infection. Recently isolated from humans (termed variants), swine viruses were shown to display great genetic and antigenic diversity, hence posing considerable public health risk. Here, we utilized and approaches to provide characterization of H1 subtype variant viruses isolated since the 2009 pandemic and discuss the findings in context with previously studied H1 subtype human isolates. The variant viruses were well adapted to replicate in the human respiratory cell line Calu-3 and the respiratory tracts of mice and ferrets. However, with respect to hemagglutinin (HA) activation pH, the variant viruses had fusion pH thresholds closer to that of most classical swine and triple-reassortant H1 isolates rather than viruses that had adapted to humans. Consistent with previous observations for swine isolates, the tested variant viruses were capable of efficient transmission between cohoused ferrets but could transmit via respiratory droplets to differing degrees. Overall, this investigation demonstrates that swine H1 viruses that infected humans possess adaptations required for robust replication and, in some cases, efficient respiratory droplet transmission in a mammalian model and therefore need to be closely monitored for additional molecular changes that could facilitate transmission among humans. This work highlights the need for risk assessments of emerging H1 viruses as they continue to evolve and cause human infections. Influenza A virus is a continuously evolving respiratory pathogen. Endemic in swine, H1 and H3 subtype viruses sporadically cause human infections. As each zoonotic infection represents an opportunity for human adaptation, the emergence of a transmissible influenza virus to which there is little or no preexisting immunity is an ongoing threat to public health. Recently isolated variant H1 subtype viruses were shown to display extensive genetic diversity and in many instances were antigenically distinct from seasonal vaccine strains. In this study, we provide characterization of representative H1N1v and H1N2v viruses isolated since the 2009 pandemic. Our results show that although recent variant H1 viruses possess some adaptation markers of concern, these viruses have not fully adapted to humans and require further adaptation to present a pandemic threat. This investigation highlights the need for close monitoring of emerging variant influenza viruses for molecular changes that could facilitate efficient transmission among humans.

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“…One possible explanation for the lack of protection is attributable to the fusion stability of each HA. For example, viruses can escape the neutralization effects of HA stem-binding bnAbs by altering their HA composition such that more acidic conditions are necessary for fusion (33)(34)(35). Theoretical pI values of the HAs vs. measured EC50 values showed that H1/SI06 has the lowest pI as well as the most unfavorable compound neutralization capability (Fig.…”

Section: Resultsmentioning

confidence: 99%

An influenza A hemagglutinin small-molecule fusion inhibitor identified by a new high-throughput fluorescence polarization screen

Yao

Kadam

Lee

et al. 2020

Preprint

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Influenza hemagglutinin (HA) glycoprotein is the primary surface antigen targeted by the host immune response and a focus for development of novel vaccines, broadly neutralizing antibodies (bnAbs) and therapeutics. HA enables viral entry into host cells via receptor binding and membrane fusion and is a validated target for drug discovery. However, to date, only a very few bona fide small molecules have been reported against the HA. To identity new antiviral lead candidates against the highly conserved fusion machinery in the HA stem, we synthesized a fluorescence-polarization probe based on a recently described neutralizing cyclic peptide P7 derived from the complementarity-determining region loops of human bnAbs FI6v3 and CR9114 against the HA stem. We then designed a robust binding assay compatible with highthroughput screening to identify molecules with low µM to nM affinity to influenza A group 1 HAs. Our simple, low-cost, and efficient in vitro assay was used to screen H1/Puerto Rico/8/1934 HA trimer against approximately 72,000 compounds. The crystal structure of H1/Puerto Rico/8/1934 HA in complex with our best hit compound F0045(S) confirmed that it binds to pockets in the HA stem similar to bnAbs FI6v3 and CR9114, cyclic peptide P7, and small molecule inhibitor JNJ4796. F0045 is enantioselective against a panel of group 1 HAs and F0045(S) exhibits in vitro neutralization activity against multiple H1N1 and H5N1 strains.Our assay, compound characterization, and small-molecule candidate should further stimulate the 2 discovery and development of new compounds with unique chemical scaffolds and enhanced influenza antiviral capabilities. Summary

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H1N1 influenza viruses varying widely in hemagglutinin stability transmit efficiently from swine to swine and to ferrets

Cited by 33 publications

References 70 publications

A single mutation in Taiwanese H6N1 influenza hemagglutinin switches binding to human‐type receptors

A single mutation in Taiwanese H6N1 influenza hemagglutinin switches binding to human‐type receptors

Comparative In Vitro and In Vivo Analysis of H1N1 and H1N2 Variant Influenza Viruses Isolated from Humans between 2011 and 2016

An influenza A hemagglutinin small-molecule fusion inhibitor identified by a new high-throughput fluorescence polarization screen

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