Structural dynamics reveal subtype-specific activation and inhibition of influenza virus hemagglutinin

Garcia, Natalie K.; Kephart, Sally; Benhaim, Mark A.; Matsui, Tsutomu; Mileant, Alexander; Guttman, Miklós; Lee, Kelly.K.

doi:10.1016/j.jbc.2023.104765

Cited by 2 publications

(3 citation statements)

References 59 publications

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“…HA head-stem epitope antibodies confer robust protection against lethal influenza challenge, demonstrating that the HA head-stem epitope must be exposed on infected cells and/or virions. Structural, biophysical, and computational approaches indicate that HA trimers transiently adopt conformations that expose epitopes normally occluded in its defined prefusion form 10–13 . Such transient fluctuations might explain how B cells and antibodies recognize ordinarily occluded epitopes 16–18,22–24 .…”

Section: Discussionmentioning

confidence: 99%

“…Nevertheless, our in vitro experiments, which used recombinant HA0 (either as soluble ectodomain or native, membrane-anchored HA on the surface of transiently-transfected cells), confirmed that head-stem interface antibodies must be able to recognize their epitope on some conformation of prefusion HA, because HA0 cannot transition to a stable postfusion structure 8 . Structural, biophysical, and computational approaches indicate that HA trimers transiently adopt conformations that expose epitopes normally occluded in the defined prefusion state 10–13 . Such transient fluctuations might explain how B cells and antibodies recognize ordinarily occluded epitopes 16,17,20,39–41 .…”

Section: Discussionmentioning

confidence: 99%

“…HA1 includes the globular HA head that contains the receptor binding site (RBS), while HA2 contains the helical stem regions that rearrange during endosomal acidification to drive fusion of viral and cellular membranes. The requirement for HA to transit through multiple conformations during fusion likely accounts for the intrinsic propensity of HA0 or HA1-HA2 to transiently explore states that deviate from its prefusion conformation, which reproducibly forms ordered protein crystal lattices that yield high-resolution structures determined by X-ray crystallography 10–13 .…”

Section: Introductionmentioning

confidence: 99%

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A protective and broadly binding antibody class engages the influenza virus hemagglutinin head at its stem interface

Simmons,

Finney,

Kotaki

et al. 2023

Preprint

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Influenza infection and vaccination impart strain-specific immunity that fails to protect against both seasonal antigenic variants and the next pandemic. However, antibodies directed to conserved sites can confer broad protection. We identify and characterize a class of human antibodies that engage a previously undescribed, conserved, epitope on the influenza hemagglutinin protein (HA). Prototype antibody S8V1-157 binds at the normally occluded interface between the HA head and stem. Antibodies to this HA head-stem interface epitope are non-neutralizingin vitrobut protect against lethal infection in mice. Their breadth of binding extends across most influenza A serotypes and seasonal human variants. Antibodies to the head-stem interface epitope are present at low frequency in the memory B cell populations of multiple donors. The immunogenicity of the epitope warrants its consideration for inclusion in improved or “universal” influenza vaccines.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

A protective and broadly binding antibody class engages the influenza virus hemagglutinin head at its stem interface

Simmons,

Finney,

Kotaki

et al. 2023

Preprint

View full text Add to dashboard Cite

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Fc-independent SARS-CoV-2 infection-enhancing antibodies decouple N-terminal and receptor-binding domains by cross-linking neighboring spikes

van Eerden,

Li,

Lusiany

et al. 2024

Preprint

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Antibody dependent enhancement (ADE) is a serious concern in vaccine development. The canonical ADE pathways are dependent on the fragment crystallizable (Fc) region of the antibody. In SARS-CoV-2 several antibodies have been discovered that inflict ADE in vitro. These antibodies target the N-terminal domain (NTD) of the SARS-CoV-2 spike protein. We previously proposed that these NTD-targeting infection-enhancing antibodies (NIEAs) cross-link neighboring spike proteins via their NTDs, and that this results in a decoupling between the NTD and receptor binding domain (RBD), facilitating the "RBD down" to "up" transition. In this study we present a combination of molecular dynamics simulations and cryogenic electron microscopy data that, together, demonstrate that NIEAs are indeed able to cross-link neighboring SARS-CoV-2 spike proteins, and that this cross-linking results in a decoupling of the NTD and RBD domains. These findings provide support for an Fc region independent ADE pathway that is not only relevant for SARS-CoV-2 but also for other viruses of which the spike proteins undergo a conformational change upon host cell entry.

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Structural dynamics reveal subtype-specific activation and inhibition of influenza virus hemagglutinin

Cited by 2 publications

References 59 publications

A protective and broadly binding antibody class engages the influenza virus hemagglutinin head at its stem interface

A protective and broadly binding antibody class engages the influenza virus hemagglutinin head at its stem interface

Fc-independent SARS-CoV-2 infection-enhancing antibodies decouple N-terminal and receptor-binding domains by cross-linking neighboring spikes

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