Influenza virus subpopulations: exchange of lethal H5N1 virus NS for H1N1 virus NS triggers de novo generation of defective-interfering particles and enhances interferon-inducing particle efficiency

J Interferon Cytokine Res. 2013 Mar;33(3):99-107. doi: 10.1089/jir.2012.0070. Epub 2012 Dec 10.

Abstract

Reassortment of influenza A viruses is known to affect viability, replication efficiency, antigenicity, host range, and virulence, and can generate pandemic strains. In this study, we demonstrated that the specific exchange of the NS gene segment from highly pathogenic A/HK/156/97 (H5N1) [E92 or E92D NS1] virus for the cognate NS gene segment of A/PR/834(H1N1) [D92 NS1] virus did not cause a significant change in the sizes of infectious particle subpopulations. However, it resulted in 2 new phenotypic changes: (1) de novo generation of large subpopulations of defective-interfering particles (DIPs); and (2) enhancement of interferon (IFN)-inducing particle efficiency leading to an order of magnitude or higher quantum (peak) yield of IFN in both avian and mammalian cells. These changes were attributed to loss of function of the H5N1-NS gene products. Most notably, the NS exchange obliterated the usual IFN-induction-suppressing capacity associated with expression of full-size NS1 proteins, and hence functionally mimicked deletions in the NS1 gene. The loss of NS1-mediated suppression of IFN induction, de novo generation of DIPs, and the concomitant enhancement of IFN-inducing particle efficiency suggest that in an attenuated background, the H5N1-NS could be used to formulate a self-adjuvanting live attenuated influenza vaccine similar to viruses with deletions in the NS1 gene.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence*
  • Animals
  • Cells, Cultured
  • Chick Embryo
  • Humans
  • Influenza A Virus, H1N1 Subtype / genetics*
  • Influenza A Virus, H1N1 Subtype / immunology
  • Influenza A Virus, H5N1 Subtype / genetics*
  • Influenza A Virus, H5N1 Subtype / immunology
  • Influenza Vaccines / genetics*
  • Influenza Vaccines / immunology
  • Interferons / immunology*
  • Sequence Deletion*
  • Viral Nonstructural Proteins / genetics*
  • Viral Nonstructural Proteins / immunology

Substances

  • Influenza Vaccines
  • NS protein, influenza virus
  • Viral Nonstructural Proteins
  • Interferons