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Maintaining pH-dependent conformational flexibility of M1 is critical for efficient influenza A virus replication

Meng-Jung Chiang1, Faik N Musayev2, Martina Kosikova1

  • 1Division of Viral Products, Office of Vaccines Research and Review, Center for Biologics Evaluation and Research, United States Food and Drug Administration, Silver Spring, MD 20993, USA.

Emerging Microbes & Infections
|December 7, 2017
PubMed

Insights

Influenza A virus replication efficiency depends on matrix protein 1 (M1) pH-dependent conformational changes. A specific mutation at position 88 maintains this flexibility, enhancing viral replication and stability, offering new antiviral targets.

Area of Science:

  • Virology
  • Structural Biology
  • Molecular Biology

Background:

  • The M gene segment of influenza A virus contributes to high replication rates.
  • Matrix protein 1 (M1) undergoes pH-dependent conformational changes crucial for virus replication, but the underlying mechanisms are not fully understood.
  • Understanding M1's role can inform strategies against influenza and improve vaccine production.

Purpose of the Study:

  • To investigate the role of M1 pH-dependent conformational changes in influenza A virus replication.
  • To elucidate the impact of specific mutations at position 88 on M1 conformation and viral fitness.
  • To identify key factors controlling M1 conformational flexibility for antiviral development.

Main Methods:

  • Comparative analysis of M1 mutants M(NLS-88R) and M(NLS-88E), differing at amino acid position 88.
  • In vitro dissociation assays of M1 from viral ribonucleoproteins (vRNPs) at varying pH.
  • Crystallographic analysis to determine M1 conformational states.
  • Assessment of viral replication efficiency and genetic stability of M1 mutants.

Main Results:

  • M(NLS-88R) M1 dissociated faster from vRNPs at higher pH and disassembled more rapidly in vitro compared to M(NLS-88E) M1.
  • Despite differences in dissociation, M(NLS-88R) M1 formed a thicker matrix layer and showed stronger association with vRNPs in assembled virions.
  • M(NLS-88R) exhibited more efficient replication and greater genetic stability than M(NLS-88E).
  • Crystallography revealed M(NLS-88R) M1 maintains pH-dependent conformational switching, while M(NLS-88E) M1 is conformationally locked.

Conclusions:

  • M1 pH-dependent conformational flexibility is critical for efficient influenza A virus replication.
  • Amino acid residue at position 88 is a key determinant of M1 pH-dependent conformational changes.
  • Targeting M1 conformational dynamics presents a potential strategy for developing novel antiviral agents against influenza.

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