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 the 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 (cryoEM) to decipher the mechanism of action of a potent HA head-directed monoclonal antibody (mAb) bound to an influenza H7 HA. The epitope of the antibody is not solvent accessible in the compact, prefusion 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 prefusion 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.

Structural Biology of Influenza Hemagglutinin: An Amaranthine Adventure

“…In addition, subtype-specific bnAbs that target the vestigial esterase subdomain [127,128], "lateral patch" epitope on HA1 [129], and the junction between the ectodomain and membrane anchor have also been identified [66]. In 2019, an H7-specific bnAb was shown to target an epitope that partly involves the HA protomer-protomer interface in HA1 [130]. Such a finding demonstrated that an antibody epitope does not need to be completely solvent exposed in the prefusion conformation.…”

Human parainfluenza virus fusion complex glycoproteins imaged in action on authentic viral surfaces

“…These intermediate states in viral entry are transient and thermodynamically unstable, making it impossible to understand these transitions using standard methods. Images of the simian virus 5 / parainfluenza virus 5 (SV5/PIV5) fusion protein intermediate state, triggered by heat and captured with a fusion-inhibitory peptide, were examined using negative stain EM [85]; more recently, multiple intermediate states of influenza hemagglutinin (HA), including the first structures of an extended trimer state, were solved using cryo-EM [43,87]. These rarely visualized transition states are significant for fundamental understanding of the viral entry process.…”

“…While well-characterized for influenza [43][44][45][46] and HIV [47][48][49][50][51][52], the structural organization of glycoproteins and their architecture on HPIV3 viral surfaces is largely unknown [1,11]. The 3-dimensional structure of the F fusion trimer from multiple paramyxoviruses, including HPIV3, has been described in both the pre-fusion and post-fusion forms [12,[53][54][55][56].…”

Prepare for the Future: Dissecting the Spike to Seek Broadly Neutralizing Antibodies and Universal Vaccine for Pandemic Coronaviruses

“…Recently, H7 was found to interact with another HA head hidden epitope that is only partly and transiently exposed in the prefusion conformation. These findings suggest that the HA trimer possesses a conformational dynamics in which different prefusion conformations (breathing) briefly expose cryptic epitopes that can be targeted by protective antibodies (Turner et al, 2019). This breathing phenomenon has also been observed in other viruses, including HCoV spike, and could help to identify new conserved sites of vulnerability (Yuan et al, 2017;Wrapp et al, 2020).…”