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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| Format: | Article |
| Language: | English |
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American Society for Microbiology
2019-12-01
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| Series: | mBio |
| Subjects: | |
| Online Access: | https://journals.asm.org/doi/10.1128/mBio.02690-19 |
| _version_ | 1818822367635308544 |
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| 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 |
| collection | DOAJ |
| 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. |
| first_indexed | 2024-12-18T23:22:58Z |
| format | Article |
| id | doaj.art-5431e290a44f41d0a90a711ffff01921 |
| institution | Directory Open Access Journal |
| issn | 2150-7511 |
| language | English |
| last_indexed | 2024-12-18T23:22:58Z |
| publishDate | 2019-12-01 |
| publisher | American Society for Microbiology |
| record_format | Article |
| series | mBio |
| spelling | doaj.art-5431e290a44f41d0a90a711ffff019212022-12-21T20:47:54ZengAmerican Society for MicrobiologymBio2150-75112019-12-0110610.1128/mBio.02690-19Antibody-Dependent Cellular Cytotoxicity-Competent Antibodies against HIV-1-Infected Cells in Plasma from HIV-Infected SubjectsFranck P. Dupuy0Sanket Kant1Alexandre Barbé2Jean-Pierre Routy3Julie Bruneau4Bertrand Lebouché5Cécile Tremblay6Marzena Pazgier7Andrés Finzi8Nicole F. Bernard9Research Institute of the McGill University Health Centre (RI-MUHC), Montreal, Quebec, CanadaResearch Institute of the McGill University Health Centre (RI-MUHC), Montreal, Quebec, CanadaResearch Institute of the McGill University Health Centre (RI-MUHC), Montreal, Quebec, CanadaResearch Institute of the McGill University Health Centre (RI-MUHC), Montreal, Quebec, CanadaDepartment of Family Medicine, Université de Montréal, Montreal, Quebec, CanadaResearch Institute of the McGill University Health Centre (RI-MUHC), Montreal, Quebec, CanadaCentre de Recherche du Centre Hospitalier de l’Université de Montréal (CRCHUM), Montreal, Quebec, CanadaInfectious Diseases Division, Department of Medicine of Uniformed Services, University of the Health Sciences, Bethesda, Maryland, USACentre de Recherche du Centre Hospitalier de l’Université de Montréal (CRCHUM), Montreal, Quebec, CanadaResearch Institute of the McGill University Health Centre (RI-MUHC), Montreal, Quebec, CanadaABSTRACT 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.https://journals.asm.org/doi/10.1128/mBio.02690-19broadly neutralizing antibodiesHIV EnvelopeADCCADCC assayCD4 binding site antibodiesCD4i antibodies |
| spellingShingle | 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 mBio broadly neutralizing antibodies HIV Envelope ADCC ADCC assay CD4 binding site antibodies CD4i antibodies |
| title | 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_short | 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 |
| topic | broadly neutralizing antibodies HIV Envelope ADCC ADCC assay CD4 binding site antibodies CD4i antibodies |
| url | https://journals.asm.org/doi/10.1128/mBio.02690-19 |
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