Potent antibody-dependent cellular cytotoxicity of a V2-specific antibody is not sufficient for protection of macaques against SIV challenge.
Fc-mediated antibody effector functions, such as antibody-dependent cellular cytotoxicity (ADCC), can contribute to the containment HIV-1 replication but whether such activities are sufficient for protection is unclear. We previously identified an antibody to the variable 2 (V2) apex of the HIV-1 En...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Public Library of Science (PLoS)
2024-01-01
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| Series: | PLoS Pathogens |
| Online Access: | https://journals.plos.org/plospathogens/article/file?id=10.1371/journal.ppat.1011819&type=printable |
| _version_ | 1797322367726256128 |
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| author | Michael W Grunst Hwi Min Gil Andres G Grandea Brian J Snow Raiees Andrabi Rebecca Nedellec Iszac Burton Natasha M Clark Sanath Kumar Janaka Nida K Keles Ryan V Moriarty Andrea M Weiler Saverio Capuano Christine M Fennessey Thomas C Friedrich Shelby L O'Connor David H O'Connor Aimee T Broman Brandon F Keele Jeffrey D Lifson Lars Hangartner Dennis R Burton David T Evans |
| author_facet | Michael W Grunst Hwi Min Gil Andres G Grandea Brian J Snow Raiees Andrabi Rebecca Nedellec Iszac Burton Natasha M Clark Sanath Kumar Janaka Nida K Keles Ryan V Moriarty Andrea M Weiler Saverio Capuano Christine M Fennessey Thomas C Friedrich Shelby L O'Connor David H O'Connor Aimee T Broman Brandon F Keele Jeffrey D Lifson Lars Hangartner Dennis R Burton David T Evans |
| author_sort | Michael W Grunst |
| collection | DOAJ |
| description | Fc-mediated antibody effector functions, such as antibody-dependent cellular cytotoxicity (ADCC), can contribute to the containment HIV-1 replication but whether such activities are sufficient for protection is unclear. We previously identified an antibody to the variable 2 (V2) apex of the HIV-1 Env trimer (PGT145) that potently directs the lysis of SIV-infected cells by NK cells but poorly neutralizes SIV infectivity. To determine if ADCC is sufficient for protection, separate groups of six rhesus macaques were treated with PGT145 or a control antibody (DEN3) by intravenous infusion followed five days later by intrarectal challenge with SIVmac239. Despite high concentrations of PGT145 and potent ADCC activity in plasma on the day of challenge, all animals became infected and viral loads did not differ between the PGT145- and DEN3-treated animals. To determine if PGT145 can protect against a neutralization-sensitive virus, two additional groups of six macaques were treated with PGT145 and DEN3 and challenged with an SIVmac239 variant with a single amino acid change in Env (K180S) that increases PGT145 binding and renders the virus susceptible to neutralization by this antibody. Although there was no difference in virus acquisition, peak and chronic phase viral loads were significantly lower and time to peak viremia was significantly delayed in the PGT145-treated animals compared to the DEN3-treated control animals. Env changes were also selected in the PGT145-treated animals that confer resistance to both neutralization and ADCC. These results show that ADCC is not sufficient for protection by this V2-specific antibody. However, protection may be achieved by increasing the affinity of antibody binding to Env above the threshold required for neutralization. |
| first_indexed | 2024-03-08T05:13:18Z |
| format | Article |
| id | doaj.art-8f8b7d273bab487cb298ce773438920f |
| institution | Directory Open Access Journal |
| issn | 1553-7366 1553-7374 |
| language | English |
| last_indexed | 2024-03-08T05:13:18Z |
| publishDate | 2024-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS Pathogens |
| spelling | doaj.art-8f8b7d273bab487cb298ce773438920f2024-02-07T05:30:51ZengPublic Library of Science (PLoS)PLoS Pathogens1553-73661553-73742024-01-01201e101181910.1371/journal.ppat.1011819Potent antibody-dependent cellular cytotoxicity of a V2-specific antibody is not sufficient for protection of macaques against SIV challenge.Michael W GrunstHwi Min GilAndres G GrandeaBrian J SnowRaiees AndrabiRebecca NedellecIszac BurtonNatasha M ClarkSanath Kumar JanakaNida K KelesRyan V MoriartyAndrea M WeilerSaverio CapuanoChristine M FennesseyThomas C FriedrichShelby L O'ConnorDavid H O'ConnorAimee T BromanBrandon F KeeleJeffrey D LifsonLars HangartnerDennis R BurtonDavid T EvansFc-mediated antibody effector functions, such as antibody-dependent cellular cytotoxicity (ADCC), can contribute to the containment HIV-1 replication but whether such activities are sufficient for protection is unclear. We previously identified an antibody to the variable 2 (V2) apex of the HIV-1 Env trimer (PGT145) that potently directs the lysis of SIV-infected cells by NK cells but poorly neutralizes SIV infectivity. To determine if ADCC is sufficient for protection, separate groups of six rhesus macaques were treated with PGT145 or a control antibody (DEN3) by intravenous infusion followed five days later by intrarectal challenge with SIVmac239. Despite high concentrations of PGT145 and potent ADCC activity in plasma on the day of challenge, all animals became infected and viral loads did not differ between the PGT145- and DEN3-treated animals. To determine if PGT145 can protect against a neutralization-sensitive virus, two additional groups of six macaques were treated with PGT145 and DEN3 and challenged with an SIVmac239 variant with a single amino acid change in Env (K180S) that increases PGT145 binding and renders the virus susceptible to neutralization by this antibody. Although there was no difference in virus acquisition, peak and chronic phase viral loads were significantly lower and time to peak viremia was significantly delayed in the PGT145-treated animals compared to the DEN3-treated control animals. Env changes were also selected in the PGT145-treated animals that confer resistance to both neutralization and ADCC. These results show that ADCC is not sufficient for protection by this V2-specific antibody. However, protection may be achieved by increasing the affinity of antibody binding to Env above the threshold required for neutralization.https://journals.plos.org/plospathogens/article/file?id=10.1371/journal.ppat.1011819&type=printable |
| spellingShingle | Michael W Grunst Hwi Min Gil Andres G Grandea Brian J Snow Raiees Andrabi Rebecca Nedellec Iszac Burton Natasha M Clark Sanath Kumar Janaka Nida K Keles Ryan V Moriarty Andrea M Weiler Saverio Capuano Christine M Fennessey Thomas C Friedrich Shelby L O'Connor David H O'Connor Aimee T Broman Brandon F Keele Jeffrey D Lifson Lars Hangartner Dennis R Burton David T Evans Potent antibody-dependent cellular cytotoxicity of a V2-specific antibody is not sufficient for protection of macaques against SIV challenge. PLoS Pathogens |
| title | Potent antibody-dependent cellular cytotoxicity of a V2-specific antibody is not sufficient for protection of macaques against SIV challenge. |
| title_full | Potent antibody-dependent cellular cytotoxicity of a V2-specific antibody is not sufficient for protection of macaques against SIV challenge. |
| title_fullStr | Potent antibody-dependent cellular cytotoxicity of a V2-specific antibody is not sufficient for protection of macaques against SIV challenge. |
| title_full_unstemmed | Potent antibody-dependent cellular cytotoxicity of a V2-specific antibody is not sufficient for protection of macaques against SIV challenge. |
| title_short | Potent antibody-dependent cellular cytotoxicity of a V2-specific antibody is not sufficient for protection of macaques against SIV challenge. |
| title_sort | potent antibody dependent cellular cytotoxicity of a v2 specific antibody is not sufficient for protection of macaques against siv challenge |
| url | https://journals.plos.org/plospathogens/article/file?id=10.1371/journal.ppat.1011819&type=printable |
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