Antibody and virus: binding and neutralization.

During infection with an enveloped virus, antibodiesare elicited to envelope proteins. Some of these antibod-ies bind to envelope spikes on the virion, some bind tononvirion forms of the envelope (“viral debris”), and somebind to both. The relative amounts of different antibodytypes elicited varies from virus to virus. There is generalagreement that only anti-envelope antibodies that bind tothe envelope spike on the virion will be neutralizing orshow antiviral activity. However, there is less agreementabout whether all antibodies that bind to the envelopespike will neutralize virus, i.e., are there antibodies thatbind well to envelope spikes but do not neutralize virus? The question is more than academic. If all antibodiesthat bind neutralize, then the envelope spike has therequisite antigenic properties of an ideal vaccine candi-date. On the other hand, if the envelope spike can inducenonneutralizing antibodies, then it may not be an optimalantigen. In particular, the induction of nonneutralizingantibodies that can bind to envelope spikes and inhibitthe binding of neutralizing antibodies would be undesir-able.Our experience, most particularly in studies on humanmonoclonal antibodies to HIV-1, RSV, and Ebola virus,has been that there is an excellent correlation betweenbinding to envelope spikes and neutralization, which inthese studies was measured as binding to infected cells(i.e., cell-associated virus). We have not encounteredmonoclonal antibodies that bind well to envelope spikeson infected cells but do not neutralize virus. Furthermore,we have generally seen a close correlation betweenhalf-maximal antibody binding and antibody concentra-tion required to give 50% neutralization suggesting thatneutralization is directly related to occupancy of sites onthe virion. For HIV-1, neutralization is incremental withincreasing antibody occupancy, irrespective of theepitope recognized, leading to increased inhibition ofinfectivity. This is consistent with a multihit neutralizationmodel rather than with a single-hit model or modelswhich predict a neutralization threshold. We have viewedantibody neutralization as a process in which virionsbecome coated with antibody and are thereby stericallyinhibited from attachment to the target cell or fusion withthe membrane of the target cell. The antibody moleculeis typically similar in size to an envelope spike, e.g., forHIV-1 the extracellular trimer has a molecular weight ofabout 450 kDa, similar to that of three IgG molecules,making steric obstruction a likely scenario. In this view, itis relatively difficult to imagine a virion coated with non-neutralizing antibodies.However, in contrast to these observations and thisdiscussion, there is a strong tradition in virology of “bind-ing (i.e., to the virion) but nonneutralizing” antibodies. Wehave wondered why we have not found evidence forsuch antibodies. Of course this could simply reflect theirabsence in the systems that we have studied. We ques-tion the evidence for nonneutralizing antibodies that bindwell to the virus.Early studies described a “nonneutralizable” fraction ofvirus which persisted even at high antibody concentra-tions. Addition of anti-antibody could reduce infectivity ofthis fraction. It seems that virus aggregation may havebeen responsible for this phenomenon. We also note thatnonneutralizable fractions have been described for hep-atitis A and hepatitis C as a result of virus associationwith lipids or lipoproteins.Undoubtedly, some descriptions of binding, nonneu-tralizing antibodies arose because of a failure to appre-ciate that antibodies that bind to isolated envelope mol-ecules do not necessarily, and very often do not, bind toenvelope spikes. A classic example is HIV-1 where manyantibodies have been described which bind with highaffinity to monomeric gp120 or unprocessed gp160, veryfew of these however showing substantial affinity forenvelope spikes.Antibody-mediated enhancement of infection is a phe-nomenon that at first glance illustrates the existence ofnonneutralizing antibodies since the antibodies involvedmust bind to virions. However, a key observation here isthat enhancement, when described, appears to occur forneutralizing antibodies at subneutralizing concentra-