eCD4-Ig promotes ADCC activity of sera from HIV-1-infected patients.
Antibody-dependent cell-mediated cytotoxity (ADCC) can eliminate HIV-1 infected cells, and may help reduce the reservoir of latent virus in infected patients. Sera of HIV-1 positive individuals include a number of antibodies that recognize epitopes usually occluded on HIV-1 envelope glycoprotein (En...
| Main Authors: | , , , |
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| Format: | Article |
| Language: | English |
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Public Library of Science (PLoS)
2017-12-01
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| Series: | PLoS Pathogens |
| Online Access: | http://europepmc.org/articles/PMC5749896?pdf=render |
| _version_ | 1828497787320270848 |
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| author | Meredith E Davis-Gardner Matthew R Gardner Barnett Alfant Michael Farzan |
| author_facet | Meredith E Davis-Gardner Matthew R Gardner Barnett Alfant Michael Farzan |
| author_sort | Meredith E Davis-Gardner |
| collection | DOAJ |
| description | Antibody-dependent cell-mediated cytotoxity (ADCC) can eliminate HIV-1 infected cells, and may help reduce the reservoir of latent virus in infected patients. Sera of HIV-1 positive individuals include a number of antibodies that recognize epitopes usually occluded on HIV-1 envelope glycoprotein (Env) trimers. We have recently described eCD4-Ig, a potent and exceptionally broad inhibitor of HIV-1 entry that can be used to protect rhesus macaques from multiple high-dose challenges with simian-human immunodeficiency virus AD8 (SHIV-AD8). Here we show that eCD4-Ig bearing an IgG1 Fc domain (eCD4-IgG1) can mediate efficient ADCC activity against HIV-1 isolates with differing tropisms, and that it does so at least 10-fold more efficiently than CD4-Ig, even when more CD4-Ig molecules bound cell surface-expressed Env. An ADCC-inactive IgG2 form of eCD4-Ig (eCD4-IgG2) exposes V3-loop and CD4-induced epitopes on cell-expressed trimers, and renders HIV-1-infected cells susceptible to ADCC mediated by antibodies of these classes. Moreover, eCD4-IgG2, but not IgG2 forms of the broadly neutralizing antibodies VRC01 and 10-1074, enhances the ADCC activities of serum antibodies from patients by 100-fold, and significantly enhanced killing of two latently infected T-cell lines reactivated by vorinostat or TNFα. Thus eCD4-Ig is qualitatively different from CD4-Ig or neutralizing antibodies in its ability to mediate ADCC, and it may be uniquely useful in treating HIV-1 infection or reducing the reservoir of latently infected cells. |
| first_indexed | 2024-12-11T12:53:54Z |
| format | Article |
| id | doaj.art-ba2ce5af2d32498cbd8de5dad08d312e |
| institution | Directory Open Access Journal |
| issn | 1553-7366 1553-7374 |
| language | English |
| last_indexed | 2024-12-11T12:53:54Z |
| publishDate | 2017-12-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS Pathogens |
| spelling | doaj.art-ba2ce5af2d32498cbd8de5dad08d312e2022-12-22T01:06:37ZengPublic Library of Science (PLoS)PLoS Pathogens1553-73661553-73742017-12-011312e100678610.1371/journal.ppat.1006786eCD4-Ig promotes ADCC activity of sera from HIV-1-infected patients.Meredith E Davis-GardnerMatthew R GardnerBarnett AlfantMichael FarzanAntibody-dependent cell-mediated cytotoxity (ADCC) can eliminate HIV-1 infected cells, and may help reduce the reservoir of latent virus in infected patients. Sera of HIV-1 positive individuals include a number of antibodies that recognize epitopes usually occluded on HIV-1 envelope glycoprotein (Env) trimers. We have recently described eCD4-Ig, a potent and exceptionally broad inhibitor of HIV-1 entry that can be used to protect rhesus macaques from multiple high-dose challenges with simian-human immunodeficiency virus AD8 (SHIV-AD8). Here we show that eCD4-Ig bearing an IgG1 Fc domain (eCD4-IgG1) can mediate efficient ADCC activity against HIV-1 isolates with differing tropisms, and that it does so at least 10-fold more efficiently than CD4-Ig, even when more CD4-Ig molecules bound cell surface-expressed Env. An ADCC-inactive IgG2 form of eCD4-Ig (eCD4-IgG2) exposes V3-loop and CD4-induced epitopes on cell-expressed trimers, and renders HIV-1-infected cells susceptible to ADCC mediated by antibodies of these classes. Moreover, eCD4-IgG2, but not IgG2 forms of the broadly neutralizing antibodies VRC01 and 10-1074, enhances the ADCC activities of serum antibodies from patients by 100-fold, and significantly enhanced killing of two latently infected T-cell lines reactivated by vorinostat or TNFα. Thus eCD4-Ig is qualitatively different from CD4-Ig or neutralizing antibodies in its ability to mediate ADCC, and it may be uniquely useful in treating HIV-1 infection or reducing the reservoir of latently infected cells.http://europepmc.org/articles/PMC5749896?pdf=render |
| spellingShingle | Meredith E Davis-Gardner Matthew R Gardner Barnett Alfant Michael Farzan eCD4-Ig promotes ADCC activity of sera from HIV-1-infected patients. PLoS Pathogens |
| title | eCD4-Ig promotes ADCC activity of sera from HIV-1-infected patients. |
| title_full | eCD4-Ig promotes ADCC activity of sera from HIV-1-infected patients. |
| title_fullStr | eCD4-Ig promotes ADCC activity of sera from HIV-1-infected patients. |
| title_full_unstemmed | eCD4-Ig promotes ADCC activity of sera from HIV-1-infected patients. |
| title_short | eCD4-Ig promotes ADCC activity of sera from HIV-1-infected patients. |
| title_sort | ecd4 ig promotes adcc activity of sera from hiv 1 infected patients |
| url | http://europepmc.org/articles/PMC5749896?pdf=render |
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