Mechanisms of Hemagglutinin Targeted Influenza Virus Neutralization

Boerries Brandenburg,Miriam V Bujny,Jarek Juraszek,Chan Tang,Jaap Goudsmit,Ted Kwaks,Wouter Koudstaal,Robert H E Friesen,Jason J Otterstrom,Hans J W M Korse,Vincent Klaren,Antoine M Van Oijen,Ronald Vogels

doi:10.1371/journal.pone.0080034

Abstract

Human monoclonal antibodies have been identified which neutralize broad spectra of influenza A or B viruses. Here, we dissect the mechanisms by which such antibodies interfere with infectivity. We distinguish four mechanisms that link the conserved hemagglutinin (HA) epitopes of broadly neutralizing antibodies to critical processes in the viral life cycle. HA-stem binding antibodies can act intracellularly by blocking fusion between the viral and endosomal membranes and extracellularly by preventing the proteolytic activation of HA. HA-head binding antibodies prevent viral attachment and release. These insights into newly identified ways by which the human immune system can interfere with influenza virus infection may aid the development of novel universal vaccines and antivirals.

Highlights

Influenza viruses continue to be a major cause of morbidity and mortality due to shortcomings of currently available vaccines and antivirals
Stem-binding broadly neutralizing antibodies (bnAbs) are internalized by live cells in complex with viral particles, reach late endosomes, and prevent infection
Stem-binding neutralizing antibodies have been postulated to inhibit the fusion process based on their interaction with the HA2 subunit and lack of activity in hemagglutination-inhibition (HAI) assays, which detect antibodies that interfere with attachment of the virus to sialic acid receptors

Summary

Introduction

Influenza viruses continue to be a major cause of morbidity and mortality due to shortcomings of currently available vaccines and antivirals. Despite the well-established role of neutralizing antibodies in the defense against influenza virus infection [1,2] there is a lack of evidence on how such antibodies interfere with infection. Further understanding of their mechanisms of action, correlated to the structures involved, may guide the design of better vaccines and antivirals. Neutralizing antibodies mainly target the hemagglutinin (HA) protein, the major envelope glycoprotein of influenza viruses. After endocytosis of the virus, acidification of the endosomes triggers large conformational changes in the HA2 ‘‘stem’’ subunit leading to fusion of the viral and endosomal membranes and release of the viral genome into the cytoplasm, allowing the infection to progress

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Conclusion