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

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-spe...

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Autores principales:	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
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2019
Materias:	ADCC antibody function human immunodeficiency virus neutralizing antibodies simian immunodeficiency virus Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/c1a57cf58e484610983b2c42b864ce7c
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spelling	oai:doaj.org-article:c1a57cf58e484610983b2c42b864ce7c2021-11-15T16:22:10ZDifferences 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 Neutralization10.1128/mBio.01255-192150-7511https://doaj.org/article/c1a57cf58e484610983b2c42b864ce7c2019-08-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.01255-19https://doaj.org/toc/2150-7511ABSTRACT 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.Benjamin von BredowRaiees AndrabiMichael GrunstAndres G. GrandeaKhoa LeGe SongZachary T. BerndsenKatelyn PorterJesper PallesenAndrew B. WardDennis R. BurtonDavid T. EvansAmerican Society for MicrobiologyarticleADCCantibody functionhuman immunodeficiency virusneutralizing antibodiessimian immunodeficiency virusMicrobiologyQR1-502ENmBio, Vol 10, Iss 4 (2019)
institution	DOAJ
collection	DOAJ
language	EN
topic	ADCC antibody function human immunodeficiency virus neutralizing antibodies simian immunodeficiency virus Microbiology QR1-502
spellingShingle	ADCC antibody function human immunodeficiency virus neutralizing antibodies simian immunodeficiency virus Microbiology QR1-502 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 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
description	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.
format	article
author	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
author_facet	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
author_sort	Benjamin von Bredow
title	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
title_short	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
title_full	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
title_fullStr	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
title_full_unstemmed	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
title_sort	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
publisher	American Society for Microbiology
publishDate	2019
url	https://doaj.org/article/c1a57cf58e484610983b2c42b864ce7c
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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

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