Potent anti-influenza H7 human monoclonal antibody induces separation of hemagglutinin receptor binding head domains

Abstract

Seasonal influenza virus infections can cause significant morbidity and mortality, but the threat from emergence of a new pandemic influenza strain might have potentially even more devastating consequences. As such, there is intense interest in isolating and characterizing potent neutralizing antibodies that target the hemagglutinin (HA) viral surface glycoprotein. Here, we use cryo-electron microscopy to decipher the mechanism of action of a potent HA head-directed monoclonal antibody bound to an influenza H7 HA. The epitope of the antibody is not solvent accessible in the compact, pre-fusion conformation that typifies all HA structures to date.Instead, the antibody binds between HA head protomers to an epitope that must be partly or transiently exposed in the pre-fusion conformation. The "breathing" of the HA protomers is implied by the exposure of this epitope, which is consistent with metastability of class I fusion proteins. This structure likely therefore represents an early structural intermediate in the viral fusion process. Understanding the extent of transient exposure of conserved neutralizing epitopes also may lead to new opportunities to combat influenza that have not been appreciated previously. Author SummaryA transiently exposed epitope on influenza H7 hemagglutinin represents a new target for neutralizing antibodies.

Cryo-EM Studies of Virus-Antibody Immune Complexes

“…Twenty antibody classes targeting six epitopes on the prefusion closed HIV-1 Env trimer have been characterized using SPA (Table 3) and crystallographic studies (Chuang et al 2019). 'Breathing' by HIV-1 B41 SOSIP.664 trimers was found to expose the b12 epitope (Ozorowski et al 2017), and a similar motion by influenza HA protomers was also revealed by SPA (Turner et al 2019). S230 binding induces fusogenic conformational rearrangements in the SARS-CoV S glycoprotein, while the MERS-CoV S glycoprotein remains its prefusion conformation upon LCA60 binding Walls et al 2019).…”

Recent advances in “universal” influenza virus antibodies: the rise of a hidden trimeric interface in hemagglutinin globular head

“…These findings suggest that the HA trimer is dynamic [88][89][90] and that the interface can be opened, perhaps transiently or partially, to expose conserved sites. The "breathing" of the interface of the HA head domain has also been reported [16][17][18]87]. HA0 is the HA precursor protein.…”

“…This interface was previously considered to be hidden but can be exposed according to the recently proposed HA "breathing" theory [16]. Consequently, panels of broadly neutralizing antibodies targeting these epitopes were identified [16][17][18]. In the present work, we review the recent progress on these novel "universal" antibodies and discuss the potential implications of existing studies on influenza drug and vaccine development.…”

“…A vast number of influenzaneutralizing antibodies against the HA globular domain are strain-specific and can efficiently prevent infection by blocking the HA-mediated attachment to cells. Examples of such antibodies include the H1-specific antibody 5J8, the H2-specific antibody 8M2, the H5-specific antibody 13D4, and the H7-specific antibody H7.5 [18,[42][43][44], whose binding sites are close to or overlap with RBSs. In 2018, an H1-specific antibody CL6649 identified another conserved site on the HA head side of the H1 subtype; this site is called a "lateral patch" [45].…”

“…Turner et al also found this mechanism by observing the process of HA binding to a potent influenza H7 HA head-directed mAb through cryoelectron microscopy. The epitope of the antibody is not solvent and accessible in the compact prefusion conformation but is transiently exposed during "breathing" [18]. In 2019, a study discovered a naturally occurring human monoclonal antibody, FluA-20, which can protect against almost all influenza types [87].…”