The high-affinity immunoglobulin receptor FcγRI potentiates HIV-1 neutralization via antibodies against the gp41 N-heptad repeat
Copyright © 2021 the Author(s). Published by PNAS..
The HIV-1 gp41 N-heptad repeat (NHR) region of the prehairpin intermediate, which is transiently exposed during HIV-1 viral membrane fusion, is a validated clinical target in humans and is inhibited by the Food and Drug Administration (FDA)-approved drug enfuvirtide. However, vaccine candidates targeting the NHR have yielded only modest neutralization activities in animals; this inhibition has been largely restricted to tier-1 viruses, which are most sensitive to neutralization by sera from HIV-1-infected individuals. Here, we show that the neutralization activity of the well-characterized NHR-targeting antibody D5 is potentiated >5,000-fold in TZM-bl cells expressing FcγRI compared with those without, resulting in neutralization of many tier-2 viruses (which are less susceptible to neutralization by sera from HIV-1-infected individuals and are the target of current antibody-based vaccine efforts). Further, antisera from guinea pigs immunized with the NHR-based vaccine candidate (ccIZN36)3 neutralized tier-2 viruses from multiple clades in an FcγRI-dependent manner. As FcγRI is expressed on macrophages and dendritic cells, which are present at mucosal surfaces and are implicated in the early establishment of HIV-1 infection following sexual transmission, these results may be important in the development of a prophylactic HIV-1 vaccine.
| Errataetall: |
CommentIn: Proc Natl Acad Sci U S A. 2021 Feb 16;118(7):. - PMID 33504595 |
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| Medienart: |
E-Artikel |
| Erscheinungsjahr: |
2021 |
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| Erschienen: |
2021 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:118 |
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| Enthalten in: |
Proceedings of the National Academy of Sciences of the United States of America - 118(2021), 3 vom: 19. Jan. |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Montefiori, David C [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 12.05.2021 Date Revised 05.10.2022 published: Print CommentIn: Proc Natl Acad Sci U S A. 2021 Feb 16;118(7):. - PMID 33504595 Citation Status MEDLINE |
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| doi: |
10.1073/pnas.2018027118 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM319951081 |
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| 100 | 1 | |a Montefiori, David C |e verfasserin |4 aut | |
| 245 | 1 | 4 | |a The high-affinity immunoglobulin receptor FcγRI potentiates HIV-1 neutralization via antibodies against the gp41 N-heptad repeat |
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| 500 | |a CommentIn: Proc Natl Acad Sci U S A. 2021 Feb 16;118(7):. - PMID 33504595 | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a Copyright © 2021 the Author(s). Published by PNAS. | ||
| 520 | |a The HIV-1 gp41 N-heptad repeat (NHR) region of the prehairpin intermediate, which is transiently exposed during HIV-1 viral membrane fusion, is a validated clinical target in humans and is inhibited by the Food and Drug Administration (FDA)-approved drug enfuvirtide. However, vaccine candidates targeting the NHR have yielded only modest neutralization activities in animals; this inhibition has been largely restricted to tier-1 viruses, which are most sensitive to neutralization by sera from HIV-1-infected individuals. Here, we show that the neutralization activity of the well-characterized NHR-targeting antibody D5 is potentiated >5,000-fold in TZM-bl cells expressing FcγRI compared with those without, resulting in neutralization of many tier-2 viruses (which are less susceptible to neutralization by sera from HIV-1-infected individuals and are the target of current antibody-based vaccine efforts). Further, antisera from guinea pigs immunized with the NHR-based vaccine candidate (ccIZN36)3 neutralized tier-2 viruses from multiple clades in an FcγRI-dependent manner. As FcγRI is expressed on macrophages and dendritic cells, which are present at mucosal surfaces and are implicated in the early establishment of HIV-1 infection following sexual transmission, these results may be important in the development of a prophylactic HIV-1 vaccine | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, N.I.H., Extramural | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 4 | |a Research Support, U.S. Gov't, Non-P.H.S. | |
| 650 | 4 | |a Fc receptor | |
| 650 | 4 | |a HIV-1 | |
| 650 | 4 | |a gp41 | |
| 650 | 4 | |a prehairpin intermediate | |
| 650 | 4 | |a vaccine | |
| 650 | 7 | |a Antibodies, Neutralizing |2 NLM | |
| 650 | 7 | |a HIV Antibodies |2 NLM | |
| 650 | 7 | |a HIV Envelope Protein gp41 |2 NLM | |
| 650 | 7 | |a Immune Sera |2 NLM | |
| 650 | 7 | |a Immunoglobulin G |2 NLM | |
| 650 | 7 | |a Receptors, IgG |2 NLM | |
| 700 | 1 | |a Filsinger Interrante, Maria V |e verfasserin |4 aut | |
| 700 | 1 | |a Bell, Benjamin N |e verfasserin |4 aut | |
| 700 | 1 | |a Rubio, Adonis A |e verfasserin |4 aut | |
| 700 | 1 | |a Joyce, Joseph G |e verfasserin |4 aut | |
| 700 | 1 | |a Shiver, John W |e verfasserin |4 aut | |
| 700 | 1 | |a LaBranche, Celia C |e verfasserin |4 aut | |
| 700 | 1 | |a Kim, Peter S |e verfasserin |4 aut | |
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