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Updated: Sep 3, 2025

Production of High-Titer Infectious Influenza Pseudotyped Particles with Envelope Glycoproteins from Highly Pathogenic H5N1 and Avian H7N9 Viruses
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Hemagglutinin Subtype Specificity and Mechanisms of Highly Pathogenic Avian Influenza Virus Genesis

Anja C M de Bruin1, Mathis Funk1, Monique I Spronken1

  • 1Department of Viroscience, Erasmus Medical Center, 3000 CA Rotterdam, The Netherlands.

Viruses
|July 27, 2022
PubMed

Insights

Highly Pathogenic Avian Influenza Viruses (HPAIVs) emerge when low pathogenic strains acquire a multi-basic cleavage site (MBCS) in their hemagglutinin (HA) protein. This change allows HPAIVs to spread systemically in poultry.

Area of Science:

  • Virology
  • Molecular Biology
  • Ecology

Background:

  • Highly Pathogenic Avian Influenza Viruses (HPAIVs) originate from low pathogenic avian influenza viruses (LPAIVs) after spillover events from wild waterfowl to domestic poultry.
  • The hemagglutinin (HA) glycoprotein's multi-basic cleavage site (MBCS) is the primary determinant of HPAIV virulence.
  • MBCS enables HA cleavage by ubiquitous proteases, leading to systemic viral dissemination in poultry.

Purpose of the Study:

  • To review recent advances in understanding HA cleavage efficiency, protease utilization, and MBCS acquisition mechanisms.
  • To discuss hypotheses explaining the H5 and H7 HA subtypes' predisposition to MBCS acquisition.
  • To compile data from natural LPAIV to HPAIV conversions and experimental studies.

Main Methods:

  • Review of natural LPAIV to HPAIV conversions.
  • Analysis of experimental in vitro studies.
  • Analysis of experimental in vivo studies.

Main Results:

  • Documented 51 independent MBCS acquisition events since 1959, predominantly in H5 and H7 HA subtypes.
  • Compilation of recent findings on HA cleavage efficiency and protease usage.
  • Discussion of potential mechanisms for MBCS acquisition.

Conclusions:

  • The acquisition of an MBCS in the HA protein is critical for the evolution of HPAIVs.
  • The H5 and H7 HA subtypes exhibit a unique susceptibility to acquiring MBCS.
  • Further research is needed to fully elucidate the molecular mechanisms driving MBCS acquisition in avian influenza viruses.
Keywords:
Highly Pathogenic Avian Influenza VirusesLow-Pathogenic Avian Influenza VirusesRNA-dependent RNA polymerasemultibasic cleavage sitepathogen evolutionproteolytic cleavagevirulence

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