Antibody-Dependent Cellular Cytotoxicity-Competent Antibodies against HIV-1-Infected Cells in Plasma from HIV-Infected Subjects

ABSTRACT Measuring Envelope (Env)-specific antibody (Ab)-dependent cellular cytotoxicity (ADCC)-competent Abs in HIV+ plasma is challenging because Env displays distinctive epitopes when present in a native closed trimeric conformation on infected cells or in a CD4-bound conformation on uninfected b...

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Autores principales:	Franck P. Dupuy, Sanket Kant, Alexandre Barbé, Jean-Pierre Routy, Julie Bruneau, Bertrand Lebouché, Cécile Tremblay, Marzena Pazgier, Andrés Finzi, Nicole F. Bernard
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2019
Materias:	broadly neutralizing antibodies HIV Envelope ADCC ADCC assay CD4 binding site antibodies CD4i antibodies Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/5431e290a44f41d0a90a711ffff01921
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spelling	oai:doaj.org-article:5431e290a44f41d0a90a711ffff019212021-11-15T15:54:45ZAntibody-Dependent Cellular Cytotoxicity-Competent Antibodies against HIV-1-Infected Cells in Plasma from HIV-Infected Subjects10.1128/mBio.02690-192150-7511https://doaj.org/article/5431e290a44f41d0a90a711ffff019212019-12-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.02690-19https://doaj.org/toc/2150-7511ABSTRACT Measuring Envelope (Env)-specific antibody (Ab)-dependent cellular cytotoxicity (ADCC)-competent Abs in HIV+ plasma is challenging because Env displays distinctive epitopes when present in a native closed trimeric conformation on infected cells or in a CD4-bound conformation on uninfected bystander cells. We developed an ADCC model which distinguishes Env-specific ADCC-competent Abs based on their capacity to eliminate infected, bystander, or Env rgp120-coated cells as a surrogate for shed gp120 on bystander cells. A panel of monoclonal Abs (MAbs), used to opsonize these target cells, showed that infected cells were preferentially recognized/eliminated by MAbs to CD4 binding site, V3 loop, and viral spike epitopes whereas bystander/coated cells were preferentially recognized/eliminated by Abs to CD4-induced (CD4i) epitopes. In HIV-positive (HIV+) plasma, Env-specific Abs recognized and supported ADCC of infected cells, though a majority were directed toward CD4i epitopes on bystander cells. For ADCC activity to be effective in HIV control, ADCC-competent Abs need to target genuinely infected cells. IMPORTANCE HIV Env-specific nonneutralizing Abs (NnAbs) able to mediate ADCC have been implicated in protection from HIV infection. However, Env-specific NnAbs have the capacity to support ADCC of both HIV-infected and HIV-uninfected bystander cells, potentially leading to misinterpretations when the assay used to measure ADCC does not distinguish between the two target cell types present in HIV cultures. Using a novel ADCC assay, which simultaneously quantifies the killing activity of Env-specific Abs on both infected and uninfected bystander cells, we observed that only a minority of Env-specific Abs in HIV+ plasma mediated ADCC of genuinely HIV-infected cells displaying Env in its native closed conformation. This assay can be used for the development of vaccine strategies aimed at eliciting Env-specific Ab responses capable of controlling HIV infection.Franck P. DupuySanket KantAlexandre BarbéJean-Pierre RoutyJulie BruneauBertrand LebouchéCécile TremblayMarzena PazgierAndrés FinziNicole F. BernardAmerican Society for Microbiologyarticlebroadly neutralizing antibodiesHIV EnvelopeADCCADCC assayCD4 binding site antibodiesCD4i antibodiesMicrobiologyQR1-502ENmBio, Vol 10, Iss 6 (2019)
institution	DOAJ
collection	DOAJ
language	EN
topic	broadly neutralizing antibodies HIV Envelope ADCC ADCC assay CD4 binding site antibodies CD4i antibodies Microbiology QR1-502
spellingShingle	broadly neutralizing antibodies HIV Envelope ADCC ADCC assay CD4 binding site antibodies CD4i antibodies Microbiology QR1-502 Franck P. Dupuy Sanket Kant Alexandre Barbé Jean-Pierre Routy Julie Bruneau Bertrand Lebouché Cécile Tremblay Marzena Pazgier Andrés Finzi Nicole F. Bernard Antibody-Dependent Cellular Cytotoxicity-Competent Antibodies against HIV-1-Infected Cells in Plasma from HIV-Infected Subjects
description	ABSTRACT Measuring Envelope (Env)-specific antibody (Ab)-dependent cellular cytotoxicity (ADCC)-competent Abs in HIV+ plasma is challenging because Env displays distinctive epitopes when present in a native closed trimeric conformation on infected cells or in a CD4-bound conformation on uninfected bystander cells. We developed an ADCC model which distinguishes Env-specific ADCC-competent Abs based on their capacity to eliminate infected, bystander, or Env rgp120-coated cells as a surrogate for shed gp120 on bystander cells. A panel of monoclonal Abs (MAbs), used to opsonize these target cells, showed that infected cells were preferentially recognized/eliminated by MAbs to CD4 binding site, V3 loop, and viral spike epitopes whereas bystander/coated cells were preferentially recognized/eliminated by Abs to CD4-induced (CD4i) epitopes. In HIV-positive (HIV+) plasma, Env-specific Abs recognized and supported ADCC of infected cells, though a majority were directed toward CD4i epitopes on bystander cells. For ADCC activity to be effective in HIV control, ADCC-competent Abs need to target genuinely infected cells. IMPORTANCE HIV Env-specific nonneutralizing Abs (NnAbs) able to mediate ADCC have been implicated in protection from HIV infection. However, Env-specific NnAbs have the capacity to support ADCC of both HIV-infected and HIV-uninfected bystander cells, potentially leading to misinterpretations when the assay used to measure ADCC does not distinguish between the two target cell types present in HIV cultures. Using a novel ADCC assay, which simultaneously quantifies the killing activity of Env-specific Abs on both infected and uninfected bystander cells, we observed that only a minority of Env-specific Abs in HIV+ plasma mediated ADCC of genuinely HIV-infected cells displaying Env in its native closed conformation. This assay can be used for the development of vaccine strategies aimed at eliciting Env-specific Ab responses capable of controlling HIV infection.
format	article
author	Franck P. Dupuy Sanket Kant Alexandre Barbé Jean-Pierre Routy Julie Bruneau Bertrand Lebouché Cécile Tremblay Marzena Pazgier Andrés Finzi Nicole F. Bernard
author_facet	Franck P. Dupuy Sanket Kant Alexandre Barbé Jean-Pierre Routy Julie Bruneau Bertrand Lebouché Cécile Tremblay Marzena Pazgier Andrés Finzi Nicole F. Bernard
author_sort	Franck P. Dupuy
title	Antibody-Dependent Cellular Cytotoxicity-Competent Antibodies against HIV-1-Infected Cells in Plasma from HIV-Infected Subjects
title_short	Antibody-Dependent Cellular Cytotoxicity-Competent Antibodies against HIV-1-Infected Cells in Plasma from HIV-Infected Subjects
title_full	Antibody-Dependent Cellular Cytotoxicity-Competent Antibodies against HIV-1-Infected Cells in Plasma from HIV-Infected Subjects
title_fullStr	Antibody-Dependent Cellular Cytotoxicity-Competent Antibodies against HIV-1-Infected Cells in Plasma from HIV-Infected Subjects
title_full_unstemmed	Antibody-Dependent Cellular Cytotoxicity-Competent Antibodies against HIV-1-Infected Cells in Plasma from HIV-Infected Subjects
title_sort	antibody-dependent cellular cytotoxicity-competent antibodies against hiv-1-infected cells in plasma from hiv-infected subjects
publisher	American Society for Microbiology
publishDate	2019
url	https://doaj.org/article/5431e290a44f41d0a90a711ffff01921
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Antibody-Dependent Cellular Cytotoxicity-Competent Antibodies against HIV-1-Infected Cells in Plasma from HIV-Infected Subjects

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