MAGADAN JG, Khurana S, Das SR, Frank GM, et al. Influenza A Virus Hemagglutinin Trimerization Completes Monomer Folding and Antigenicity. J Virol. 2013 Jul 3
Influenza A virus (IAV) remains an important human pathogen largely due to antigenic drift: the rapid emergence of antibody escape mutants which precludes durable vaccination. The most potent neutralizing antibodies interact with cognate epitopes in the globular ´head´ domain of hemagglutinin (HA), a homotrimeric glycoprotein. The H1 HA possesses five distinct regions defined by a large number of mouse monoclonal antibodies (mAbs): Ca1, Ca2, Cb, Sa, and Sb. Ca1-Ca2 sites require trimerization to attain full antigenicity, consistent with their locations on opposite sides of the trimer interface. Here, we show that full antigenicity of Cb and Sa sites also requires trimerization, as revealed by immunofluorescence microscopy of IAV-infected cells and biochemically by pulse-chase radiolabelling experiments. Surprisingly, epitope antigenicity acquired by trimerization persists following acid triggering of HA globular domains dissociation, and even after proteolytic release of monomeric heads from acid-treated HA. Thus, the requirement for HA trimerization by trimer-specific mAbs mapping to Ca, Cb, and Sa sites is not dependent upon bridging adjacent monomers in the native HA trimer. Rather, complete antigenicity of HA (and by inference immunogenicity) requires a final folding step that accompanies its trimerization. Once this conformational change occurs, HA trimers themselves would not necessarily be required to induce a highly diverse neutralizing response against epitopes in the globular domain.
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