Scientific article
Open access

H5N1 influenza A virus PB1-F2 relieves HAX-1-mediated restriction of avian virus polymerase PA in human lung cells

Published inJournal of Virology, vol. 92, no. 11, p. e00425-18
Publication date2018

Highly pathogenic influenza A viruses (IAV) from avian hosts were first reported to directly infect humans 20 years ago. However, such infections are rare events, and our understanding of factors promoting or restricting zoonotic transmission is still limited. One accessory protein of IAV, PB1-F2, was associated with pathogenicity of pandemic and zoonotic IAV. This short (90-amino-acid) peptide does not harbor an enzymatic function. We thus identified host factors interacting with H5N1 PB1-F2, which could explain its importance for virulence. PB1-F2 binds to HCLS1-associated protein X1 (HAX-1), a recently identified host restriction factor of the PA subunit of IAV polymerase complexes. We demonstrate that the PA of a mammal-adapted H1N1 IAV is resistant to HAX-1 imposed restriction, while the PA of an avian-origin H5N1 IAV remains sensitive. We also showed HAX-1 sensitivity for PAs of A/Brevig Mission/1/1918 (H1N1) and A/Shanghai/1/2013 (H7N9), two avian-origin zoonotic IAV. Inhibition of H5N1 polymerase by HAX-1 can be alleviated by its PB1-F2 through direct competition. Accordingly, replication of PB1-F2-deficient H5N1 IAV is attenuated in the presence of large amounts of HAX-1. Mammal-adapted H1N1 and H3N2 viruses do not display this dependence on PB1-F2 for efficient replication in the presence of HAX-1. We propose that PB1-F2 plays a key role in zoonotic transmission of avian H5N1 IAV into humans.IMPORTANCE Aquatic and shore birds are the natural reservoir of influenza A viruses from which the virus can jump into a variety of bird and mammal host species, including humans. H5N1 influenza viruses are a good model for this process. They pose an ongoing threat to human and animal health due to their high mortality rates. However, it is currently unclear what restricts these interspecies jumps on the host side or what promotes them on the virus side. Here we show that a short viral peptide, PB1-F2, helps H5N1 bird influenza viruses to overcome a human restriction factor of the viral polymerase complex HAX-1. Interestingly, we found that human influenza A virus polymerase complexes are already adapted to HAX-1 and do not require this function of PB1-F2. We thus propose that a functional full-length PB1-F2 supports direct transmission of bird viruses into humans.

  • A549 Cells
  • Adaptor Proteins
  • Signal Transducing/genetics/metabolism
  • Animals
  • Birds
  • CRISPR-Cas Systems
  • Cell Line
  • Tumor
  • Dogs
  • Gene Knockout Techniques
  • HEK293 Cells
  • HeLa Cells
  • Humans
  • Influenza A Virus
  • H1N1 Subtype/metabolism
  • Influenza A Virus
  • H3N2 Subtype/metabolism
  • Influenza A Virus
  • H5N1 Subtype/metabolism/pathogenicity
  • Influenza A Virus
  • H7N9 Subtype/metabolism
  • Influenza in Birds/transmission/virology
  • Influenza
  • Human/transmission/virology
  • Lung/virology
  • Madin Darby Canine Kidney Cells
  • Protein Binding
  • Viral Proteins/genetics/metabolism
  • Virus Replication/genetics
  • Zoonoses/transmission/virology
  • Swiss National Science Foundation - 3100030_155949
Citation (ISO format)
MAZEL-SANCHEZ, Beryl et al. H5N1 influenza A virus PB1-F2 relieves HAX-1-mediated restriction of avian virus polymerase PA in human lung cells. In: Journal of Virology, 2018, vol. 92, n° 11, p. e00425–18. doi: 10.1128/JVI.00425-18
Main files (1)
Article (Published version)
Secondary files (2)
ISSN of the journal0022-538X

Technical informations

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