Antibodies to the buried N terminus of rhinovirus VP4 exhibit cross-serotypic neutralization.
Development of a vaccine for the common cold has been thwarted by the fact that there are more than 100 serotypes of human rhinovirus (HRV). We previously demonstrated that the HRV14 capsid is dynamic and transiently displays the buried N termini of viral protein 1 (VP1) and VP4. Here, further evidence for this "breathing" phenomenon is presented, using antibodies to several peptides representing the N terminus of VP4. The antibodies form stable complexes with intact HRV14 virions and neutralize infectivity. Since this region of VP4 is highly conserved among all of the rhinoviruses, antiviral activity by these anti-VP4 antibodies is cross-serotypic. The antibodies inhibit HRV16 infectivity in a temperature- and time-dependent manner consistent with the breathing behavior. Monoclonal and polyclonal antibodies raised against the 30-residue peptide do not react with peptides shorter than 24 residues, suggesting that these peptides are adopting three-dimensional conformations that are highly dependent upon the length of the peptide. Furthermore, there is evidence that the N termini of VP4 are interacting with each other upon extrusion from the capsid. A Ser5Cys mutation in VP4 yields an infectious virus that forms cysteine cross-links in VP4 when the virus is incubated at room temperature but not at 4 degrees C. The fact that all of the VP4s are involved in this cross-linking process strongly suggests that VP4 forms specific oligomers upon extrusion. Together these results suggest that it may be possible to develop a pan-serotypic peptide vaccine to HRV, but its design will likely require details about the oligomeric structure of the exposed termini.
Katpally
Umesh
U
The Donald Danforth Plant Science Center, St Louis, MO 63132, USA.
Fu
Tong-Ming
TM
Freed
Daniel C
DC
Casimiro
Danilo R
DR
Smith
Thomas J
TJ
D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D000818:Animals; D000914:Antibodies, Viral / Q000276:immunology*; D036022:Capsid Proteins / Q000737:chemistry / Q000235:genetics / Q000276:immunology*; D002460:Cell Line; D003429:Cross Reactions; D018604:Epitope Mapping; D006801:Humans; D008969:Molecular Sequence Data; D009500:Neutralization Tests; D010850:Picornaviridae Infections / Q000276:immunology* / Q000821:virology; D011817:Rabbits; D012229:Rhinovirus / Q000737:chemistry / Q000235:genetics / Q000276:immunology*
D000914:Antibodies, Viral; D036022:Capsid Proteins