Differences in the Binding Affinity of an HIV-1 V2 Apex-Specific Antibody for the SIV$_{\textrm{smm/Mac}}$ Envelope Glycoprotein Uncouple Antibody-Dependent Cellular Cytotoxicity from Neutralization

Abstract

As a consequence of their independent evolutionary origins in apes and Old World monkeys, human immunodeficiency virus type 1 (HIV-1) and simian immunodeficiency viruses of the SIVsmm/Mac lineage express phylogenetically and antigenically distinct envelope glycoproteins. Thus, HIV-1 Env-specific antibodies do not typically cross-react with the Env proteins of SIVsmm/Mac isolates. Here we show that PGT145, a broadly neutralizing antibody to a quaternary epitope at the V2 apex of HIV-1 Env, directs the lysis of SIVsmm/mac-infected cells by antibody-dependent cellular cytotoxicity (ADCC) but does not neutralize SIVsmm/Mac infectivity. Amino acid substitutions in the V2 loop of SIV${\textrm{mac}}239correspondingtotheepitopeforPGT145inHIV−1Envmodulatesensitivitytothisantibody.WhereasasubstitutioninaconservedN−linkedglycosylationsite(N171Q)eliminatessensitivitytoADCC,alysine−to−serinesubstitutioninthisregion(K180S)increasesADCCandrendersthevirussusceptibletoneutralization.ThesedifferencesinfunctioncorrelatewithanincreaseintheaffinityofPGT145bindingtoEnvonthesurfaceofvirus−infectedcellsandtosolubleEnvtrimers.Toourknowledge,thisrepresentsthefirstinstanceofanHIV−1Env−specificantibodythatcross−reactswithSIV{\textrm{smm/Mac}}$ Env and illustrates how differences in antibody binding affinity for Env can differentiate sensitivity to ADCC from neutralization. IMPORTANCE Here we show that PGT145, a potent broadly neutralizing antibody to HIV-1, directs the lysis of SIV-infected cells by antibody-dependent cellular cytotoxicity but does not neutralize SIV infectivity. This represents the first instance of cross-reactivity of an HIV-1 Env-specific antibody with SIVsmm/Mac Env and reveals that antibody binding affinity can differentiate sensitivity to ADCC from neutralization.