Transient opening of trimeric prefusion RSV F proteins

Abstract

The respiratory syncytial virus (RSV) F glycoprotein is a class I fusion protein that mediates viral entry and is a major target of neutralizing antibodies. Structures of prefusion forms of RSV F, as well as other class I fusion proteins, have revealed compact trimeric arrangements, yet whether these trimeric forms can transiently open remains unknown. Here, we perform structural and biochemical studies on a recently isolated antibody, CR9501, and demonstrate that it enhances the opening of prefusion-stabilized RSV F trimers. The 3.3 Å crystal structure of monomeric RSV F bound to CR9501, combined with analysis of over 25 previously determined RSV F structures, reveals a breathing motion of the prefusion conformation. We also demonstrate that full-length RSV F trimers transiently open and dissociate on the cell surface. Collectively, these findings have implications for the function of class I fusion proteins, as well as antibody prophylaxis and vaccine development for RSV.

Comparisons of Antibody Populations in Different Pre-Fusion F VLP-Immunized Cotton Rat Dams and Their Offspring

“…However, DS-Cav1 F VLP sera only very weakly blocked D25 binding to the UC-3 F target, while the UC-3 F VLP sera had a very high concentration of antibodies that blocked D25 binding to the UC-3 target. This result may indicate that UC-3 F VLP vaccination generates a broader spectrum of antibodies that are capable of recognizing alternate conformations of site φ [36,37]. As expected, the sera from post-F VLP immunizations weakly blocked AM14 binding compared to other sera, had no detectable levels of D25-blocking antibodies, and served as a negative control for these experiments.…”

“…The UC-3 F VLPs induced antibodies that blocked D25 binding to both targets, while the DS-Cav1 F VLP induced sera that only very weakly blocked D25 binding to the UC-3 F target. The ability of the UC-3 F VLP sera to effectively block the binding to the two targets in contrast to DS-Cav1 F VLP sera may indicate that antibodies in the UC-3 F VLP sera more broadly recognize different conformations of site φ in the pre-fusion F proteins [36] and may contribute to the increased NAb in dams and the increased protection from RSV challenge of the offspring of these dams.…”

“…However, DS-Cav1 F VLP sera only very weakly blocked D25 binding to the UC-3 F target, while the UC-3 F VLP sera had a very high concentration of antibodies that blocked D25 binding to the UC-3 target. This result may indicate that UC-3 F VLP vaccination generates a broader spectrum of antibodies that are capable of recognizing alternate conformations of site φ [36,37]. As controls, we compared the blocking of mAb AM 14 (Figure 2, panels C and D) and palivizumab (Figure 2, panels E and F) binding to both targets using DS-Cav1 F VLP or UC-3 F VLP sera.…”

Moments of multiplicity distributions using Tsallis statistics in leptonic and hadronic collisions

“…The Tsallis distribution calculated from equation (6) is fitted to the experimental data on multiplicity distributions at each of the energies. The multiplicity distribution obtained from the Tsallis model is then used to calculate the moments of the distribution using equations (2) and (3). Figure 3 shows the dependence of normalised and factorial moments on the centre of mass energy √ s, calculated by using i) the Tsallis model and also ii) experimental distributions for e + e − data.…”

“…In high energy collisions, particles are made to collide with relativistic momenta much greater than their rest masses resulting in the production of large number of particles in final state [1] from a variety of processes. These collisions can be hadronic, leptonic or heavy-ion interactions; summarized in the form of reaction, for leptonic collision as l-l → X [2], where l is the lepton or for hadronic collisions as h-h → X [3], where h is the hadron or for hadron-nucleus collision as h-A → X [4], with A being the nucleus. X in the final state of these reactions represents any number of particles, produced due to the gluon-gluon, quark-quark and quark-gluon interactions between the constituent quarks and gluons of the colliding particles.…”