Differences in the Binding Affinity of an HIV-1 V2 Apex-Specific Antibody for the SIV<sub>smm/mac</sub> Envelope Glycoprotein Uncouple Antibody-Dependent Cellular Cytotoxicity from Neutralization
Benjamin von Bredow,
Raiees Andrabi,
Michael Grunst,
Andres G. Grandea,
Khoa Le,
Ge Song,
Zachary T. Berndsen,
Katelyn Porter,
Jesper Pallesen,
Andrew B. Ward,
Dennis R. Burton,
David T. Evans
Affiliations
Benjamin von Bredow
Department of Pathology and Laboratory Medicine, University of Wisconsin, Madison, Wisconsin, USA
Raiees Andrabi
Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, California, USA
Michael Grunst
Department of Pathology and Laboratory Medicine, University of Wisconsin, Madison, Wisconsin, USA
Andres G. Grandea
Department of Pathology and Laboratory Medicine, University of Wisconsin, Madison, Wisconsin, USA
Khoa Le
Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, California, USA
Ge Song
Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, California, USA
Zachary T. Berndsen
International AIDS Vaccine Initiative Neutralizing Antibody Center, the Collaboration for AIDS Vaccine Discovery (CAVD) and Center for HIV/AIDS Vaccine Immunology-Immunogen Discovery (CHAVI-ID), The Scripps Research Institute, La Jolla, California, USA
Katelyn Porter
Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, California, USA
Jesper Pallesen
International AIDS Vaccine Initiative Neutralizing Antibody Center, the Collaboration for AIDS Vaccine Discovery (CAVD) and Center for HIV/AIDS Vaccine Immunology-Immunogen Discovery (CHAVI-ID), The Scripps Research Institute, La Jolla, California, USA
Andrew B. Ward
International AIDS Vaccine Initiative Neutralizing Antibody Center, the Collaboration for AIDS Vaccine Discovery (CAVD) and Center for HIV/AIDS Vaccine Immunology-Immunogen Discovery (CHAVI-ID), The Scripps Research Institute, La Jolla, California, USA
Dennis R. Burton
Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, California, USA
David T. Evans
Department of Pathology and Laboratory Medicine, University of Wisconsin, Madison, Wisconsin, USA
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 SIVmac239 corresponding to the epitope for PGT145 in HIV-1 Env modulate sensitivity to this antibody. Whereas a substitution in a conserved N-linked glycosylation site (N171Q) eliminates sensitivity to ADCC, a lysine-to-serine substitution in this region (K180S) increases ADCC and renders the virus susceptible to neutralization. These differences in function correlate with an increase in the affinity of PGT145 binding to Env on the surface of virus-infected cells and to soluble Env trimers. To our knowledge, this represents the first instance of an HIV-1 Env-specific antibody that cross-reacts with SIVsmm/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.
