Antigenic and sequence variability of the human respiratory syncytial virus F glycoprotein compared to related viruses in a comprehensive dataset

Abstract

A comprehensive analysis of sequence variation was carried out comparing the fusion (F) protein of human respiratory syncytial viruses (hRSV) from antigenic groups A and B with the prototype sequence of the A2 strain, also belonging to antigenic group A. The limited number of full bovine RSV F sequences available were included, as well as an extensive set of F sequences from the related human metapneumovirus (hMPV). The results were analysed in the context of the recently determined three dimensional F protein structures, with antigenic sites mapped to these. Although a high degree of sequence conservation in hRSV F exists, and sequence changes did not correlate with location of antigenic sites, preferential accumulation of amino acid changes in certain antigenic sites was noted. When the analysis was extended to hMPV F, a high number of changes was noticed, in agreement with the limited degree of sequence conservation. However, some conserved regions were noted, which may account for the limited number of cross-reactive monoclonal antibodies described between hRSV F and hMPV F. These results provide information about the degree of sequence and antigenic variation currently found in the F protein of circulating viruses. They highlight the importance of establishing a baseline dataset to monitor for future changes that might evolve should preventative immunological measures be made widely available.

Characterization of potent RSV neutralizing antibodies isolated from human memory B cells and identification of diverse RSV/hMPV cross-neutralizing epitopes

“…Outside this conserved patch, previous analysis of a large number of sequences revealed that site Ø of RSV F is the most variable site with divergent sequences. 54 A recent report of two new site Ø mAbs with different RSV A and B specificities also highlighted the structural variations of this antigenic site. 45 Among the isolated highly potent mAbs in this study, we indeed found that mAbs targeting site Ø showed the most variations in neutralization potencies between the two different RSV subtypes, including a strain A-specific mAb 139B8.…”

A potent broadly neutralizing human RSV antibody targets conserved site IV of the fusion glycoprotein

“…A study by A. Hause et al 22 compared the F sequences of over 1000 viral isolates found that site IV was highly conserved (>99%) across all genotypes. Furthermore, a study by V. Mas et al 23 found that sites III and IV were the most conserved regions of the protein. They further argued that pre- and post-F share secondary structural elements within sites III and IV and these constitute the inter-protomeric cavity of the protein.…”

“…Sites III and IV of the protein are conserved to some extent between RSV A, B, and the related virus HMPV; therefore, they may also be required for genetic stability. In contrast, placement of site Ø and V on the apex region may require structure flexibility resulting in less conserved sequences 23 .…”

“…A study by A. Hause et al 22 , comparing the F protein sequences in over 1000 isolates found that site IV was highly conserved (>99%) across all genotypes. Furthermore, a study by V. Mas et al 23 found that sites III and IV were the most conserved regions of the protein. Since a single amino acid change can have a high impact on antibody binding, a monoclonal antibody which binds to a highly conserved epitope is more desirable and decreases the risk of emerging antibody-resistant viruses.…”

Crystal Structure and Immunogenicity of the DS-Cav1-Stabilized Fusion Glycoprotein From Respiratory Syncytial Virus Subtype B

“…By contrast, there were 5 residues in the prefusion-specific site Ø with significant entropy (Figure 5B). This scarcity of sequence variation in most antigenic sites except site Ø has been observed in an analysis of RSV clinical isolates [70].…”