pH-controlled two-step uncoating of influenza virus

Sai Li, Christian Sieben, Kai Ludwig, Chris T. Höfer, Salvatore Chiantia, Andreas Herrmann, Frederic Eghiaian*, Iwan A T Schaap

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

96 Citations (Scopus)


Upon endocytosis in its cellular host, influenza A virus transits via early to late endosomes. To efficiently release its genome, the composite viral shell must undergo significant structural rearrangement, but the exact sequence of events leading to viral uncoating remains largely speculative. In addition, no change in viral structure has ever been identified at the level of early endosomes, raising a question about their role. We performed AFM indentation on single viruses in conjunction with cellular assays under conditions that mimicked gradual acidification from early to late endosomes. We found that the release of the influenza genome requires sequential exposure to the pH of both early and late endosomes, with each step corresponding to changes in the virus mechanical response. Step 1 (pH 7.5-6) involves a modification of both hemagglutinin and the viral lumen and is reversible, whereas Step 2 (pH <6.0) involves M1 dissociation and major hemagglutinin conformational changes and is irreversible. Bypassing the early-endosomal pH step or blocking the envelope proton channel M2 precludes proper genome release and efficient infection, illustrating the importance of viral lumen acidification during the early endosomal residence for influenza virus infection.

Original languageEnglish
Pages (from-to)1447-1456
Number of pages10
JournalBiophysical Journal
Issue number7
Publication statusPublished - 1 Apr 2014

ASJC Scopus subject areas

  • Biophysics


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