Abstract
The respiratory syncytial virus (RSV) fusion (F) glycoprotein is a major target of neutralizing antibodies arising from natural infection, and antibodies that specifically bind to the prefusion conformation of RSV F generally demonstrate the greatest neutralization potency. Prefusion-stabilized RSV F variants have been engineered as vaccine antigens, but crystal structures of these variants have revealed conformational differences in a key antigenic site located at the apex of the trimer, referred to as antigenic site Ø. Currently, it is unclear if flexibility in this region is an inherent property of prefusion RSV F or if it is related to inadequate stabilization of site Ø in the engineered variants. Therefore, we set out to investigate the conformational flexibility of antigenic site Ø, as well as the ability of the human immune system to recognize alternative conformations of this site, by determining crystal structures of prefusion RSV F bound to neutralizing human-derived antibodies AM22 and RSD5. Both antibodies bound with high affinity and were specific for the prefusion conformation of RSV F. Crystal structures of the complexes revealed that the antibodies recognized distinct conformations of antigenic site Ø, each diverging at a conserved proline residue located in the middle of an α-helix. These data suggest that antigenic site Ø exists as an ensemble of conformations, with individual antibodies recognizing discrete states. Collectively, these results have implications for the refolding of pneumovirus and paramyxovirus fusion proteins and should inform development of prefusion-stabilized RSV F vaccine candidates.
Highlights
Respiratory syncytial virus (RSV) is a ubiquitous pneumovirus which infects most children in the U.S by the age of two, with repeated infections occurring throughout life [1]
Despite its prevalence, there is no vaccine for RSV and the only available therapy is limited to high-risk infants, leaving the vast majority of people with no effective means of prevention or treatment
AM22 and RSD5-GL bind with high affinity to prefusion RSV F
Summary
Respiratory syncytial virus (RSV) is a ubiquitous pneumovirus which infects most children in the U.S by the age of two, with repeated infections occurring throughout life [1]. RSV has two major glycoproteins on the viral surface important for entry: the fusion (F) and attachment (G) glycoproteins [7]. RSV F is a class I fusion glycoprotein initially produced as an inactive precursor, F0, that is subsequently cleaved by furin-like proteases to generate a protomer of disulfide-linked subunits, F1 and F2 [9,10,11,12]. Three of these protomers associate to form the functional trimeric glycoprotein required for membrane fusion and infection [13,14,15]. Numerous vaccine trials for RSV are currently underway [16], many of which contain the RSV F glycoprotein as an antigen because it has been shown that F is a major target of neutralizing antibodies [17, 18] and is the only protein on the viral surface that is strictly required for entry [19, 20]
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