Abstract
Our understanding of the neutralizing antibody response to the Fusion (F) protein of Respiratory Syncytial Virus (RSV) is still incomplete. The RSV F protein is unique as it contains adjacent to the fusion peptide not one but two furin protease cleavage sites, separated by a 27 amino acid (aa) peptide (p27). Maturation of the protein is associated with removal of p27 from the F protein which also activates the prefusion state. The exact role of p27 and the benefit for the virus are not known. Surprisingly, p27 contains 2 to 3 N-linked glycosylation sites and data from the lab of the promotor show that removal of these glycosylation sites increases neutralizing antibody responses.
How removal of glycosylation sites, in a peptide that is considered not to be present in the mature F protein, affects neutralizing antibody responses is unknown.
Preliminary data suggest that removal of these N-linked glycosylation sites affects cleavage of the p27 peptide and that this may stabilize the F protein in a flexible prefusion configuration, which may expose novel neutralizing epitopes and increase exposure of known epitopes to the immune system. This hypothesis will be investigated with a combination of in vitro and in vivo experiments using a panel of mutant F proteins, monoclonal antibodies and recombinant viruses. Further, the structure of the flexible prefusion conformation and neutralizing epitopes involved will be identified, which can drive development of novel vaccines.
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