Cross-neutralizing human anti-poliovirus antibodies bind the recognition site for cellular receptor

Abstract

Most structural information about poliovirus interaction with neutralizing antibodies was obtained in the 1980s in studies of mouse monoclonal antibodies. Recently we have isolated a number of human/chimpanzee anti-poliovirus antibodies and demonstrated that one of them, MAb A12, could neutralize polioviruses of both serotypes 1 and 2. This communication presents data on isolation of an additional cross-neutralizing antibody (F12) and identification of a previously unknown epitope on the surface of poliovirus virions. Epitope mapping was performed by sequencing of antibody-resistant mutants and by cryo-EM of complexes of virions with Fab fragments. The results have demonstrated that both cross-neutralizing antibodies bind the site located at the bottom of the canyon surrounding the fivefold axis of symmetry that was previously shown to interact with cellular poliovirus receptor CD155. However, the same antibody binds to serotypes 1 and 2 through different specific interactions. It was also shown to interact with type 3 poliovirus, albeit with about 10-fold lower affinity, insufficient for effective neutralization. Antibody interaction with the binding site of the cellular receptor may explain its broad reactivity and suggest that further screening or antibody engineering could lead to a universal antibody capable of neutralizing all three serotypes of poliovirus.phage display | passive immunization | antiviral therapy | broadly reactive antibodies T he worldwide campaign to eradicate poliomyelitis seeks to stop transmission of wild strains and to eliminate vaccinederived polioviruses (VDPVs). The latter continuously emerge from oral polio vaccine (OPV) and threaten sustainability of polio eradication, which will not be complete until OPV use is stopped (1). Besides circulating VDPVs that cause outbreaks of paralytic disease (2), there are also immunodeficiency-associated VDPVs continuously excreted by chronically infected patients with certain types of immune disorders (3), and VDPVs of unknown origin isolated from environmental samples, possibly also excreted by chronic shedders. Treatment of immunodeficient carriers is a critically important challenge that requires development of new therapeutic tools, which could also be used for posteradication risk management and rapid response to potential reemergence of poliovirus.New treatments could include antiviral drugs and biologicals, for instance antibodies. Passive immunotherapy against polio was shown to be highly effective in the early 1950s (4) but was not used after introduction of vaccines. Recently we isolated neutralizing chimpanzee-human monoclonal antibodies against poliovirus and proposed that they may be used for this purpose (5). Among antibodies isolated by phage-display technology, the antibody designated A12 neutralized two serotypes of poliovirus (types 1 and 2) and could also weakly bind type 3 poliovirus. Here we describe isolation of another cross-neutralizing antibody and demonstrate that they both bind to an epitope that is located in the reg...

Characterization of Poliovirus Neutralization Escape Mutants of Single-Domain Antibody Fragments (VHHs)

“…It is interesting that when primate antibodies were identified that cross-neutralize both poliovirus serotypes 1 and 2 (thereby avoiding the usual highly exposed antigenic sites), the antibody binding sites overlapped that of the receptor, and the escape substitutions included residues 65, 109, and 166 of VP1 (37,38). These findings clearly are very similar to our results using neutralizing VHHs and suggest that the mechanisms of neutralization are similar.…”

Convergent immunological solutions to Argentine hemorrhagic fever virus neutralization

“…Similarly, neutralizing RBS-targeting antibodies of differing germline origins have been observed in other viruses, including influenza virus, HIV, and poliovirus (32)(33)(34). In the case of influenza virus, it has been possible to recognize a signature binding motif on the CDR H3 loop (33).…”

Single Neutralizing Monoclonal Antibodies Targeting the VP1 GH Loop of Enterovirus 71 Inhibit both Virus Attachment and Internalization during Viral Entry

“…However, for nonenveloped viruses, neutralizing MAbs usually target one particular step of entry (41,44). For example, MAbs against enteroviruses mostly inhibited the attachment step (41,45,46), whereas a few antibodies which target the internal epitopes within VP1 or VP4 were suggested to exhibit neutralization only at the postattachment stage by inhibiting conformation transitions (47)(48)(49). Interestingly, in the present study we found that a group of anti-EV71 MAbs (represented by D5) exhibited neutralization at both the pre-and postattachment stages in a cell type-independent manner.…”