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Germline-targeting HIV-1 Env vaccination induces VRC01-class antibodies with rare insertions

Germline-targeting HIV-1 Env vaccination induces VRC01-class antibodies with rare insertions
Germline-targeting HIV-1 Env vaccination induces VRC01-class antibodies with rare insertions

Targeting germline (gl-) precursors of broadly neutralizing antibodies (bNAbs) is acknowledged as an important strategy for HIV-1 vaccines. The VRC01-class of bNAbs is attractive because of its distinct genetic signature. However, VRC01-class bNAbs often require extensive somatic hypermutation, including rare insertions and deletions. We describe a BG505 SOSIP trimer, termed GT1.2, to optimize binding to gl-CH31, the unmutated common precursor of the CH30-34 bNAb lineage that acquired a large CDRH1 insertion. The GT1.2 trimer activates gl-CH31 naive B cells in knock-in mice, and B cell responses could be matured by selected boosting immunogens to generate cross-reactive Ab responses. Next-generation B cell sequencing reveals selection for VRC01-class mutations, including insertions in CDRH1 and FWR3 at positions identical to VRC01-class bNAbs, as well as CDRL1 deletions and/or glycine substitutions to accommodate the N276 glycan. These results provide proof of concept for vaccine-induced affinity maturation of B cell lineages that require rare insertions and deletions.

HIV antibodies, HIV seropositivity, HIV-1/genetics, animals, antibodies, neutralizing, broadly neutralizing antibodies, mice, vaccination, insertions, mouse model, deletions, vaccines, neutralizing antibodies, bNAbs, germline-targeting, NGS, HIV-1 Env
2666-3791
101003
Caniels, Tom G.
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Medina-Ramírez, Max
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Zhang, Jinsong
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Sarkar, Anita
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Kumar, Sonu
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LaBranche, Alex
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Derking, Ronald
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Allen, Joel D.
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Diaz, Marilyn
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Aldon, Yoann
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Bijl, Tom P L.
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Newman, Amanda
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Jiang, Chuancang
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Pater, Maarten
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Burger, Judith A.
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van Breemen, Mariëlle J.
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de Taeye, Steven W.
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Rantalainen, Kimmo
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LaBranche, Celia
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Saunders, Kevin O.
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Montefiori, David
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Ozorowski, Gabriel
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Ward, Andrew B.
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Crispin, Max
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Klasse, Per Johan
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Haynes, Barton F.
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Wilson, Ian A.
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Wiehe, Kevin
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Verkoczy, Laurent
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Sanders, Rogier W.
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Caniels, Tom G.
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Medina-Ramírez, Max
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Zhang, Jinsong
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Sarkar, Anita
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Kumar, Sonu
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LaBranche, Alex
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Derking, Ronald
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Allen, Joel D.
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Snitselaar, Jonne L.
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Capella-Pujol, Joan
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Sánchez, Iván Del Moral
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Yasmeen, Anila
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Diaz, Marilyn
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Aldon, Yoann
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Bijl, Tom P L.
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Venkatayogi, Sravani
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Martin Beem, Joshua S.
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Newman, Amanda
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Jiang, Chuancang
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Lee, Wen-Hsin
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Pater, Maarten
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Burger, Judith A.
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van Breemen, Mariëlle J.
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de Taeye, Steven W.
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Rantalainen, Kimmo
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LaBranche, Celia
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Saunders, Kevin O.
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Montefiori, David
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Ozorowski, Gabriel
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Ward, Andrew B.
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Crispin, Max
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Moore, John P.
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Klasse, Per Johan
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Haynes, Barton F.
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Wilson, Ian A.
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Wiehe, Kevin
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Verkoczy, Laurent
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Caniels, Tom G., Medina-Ramírez, Max, Zhang, Jinsong, Sarkar, Anita, Kumar, Sonu, LaBranche, Alex, Derking, Ronald, Allen, Joel D., Snitselaar, Jonne L., Capella-Pujol, Joan, Sánchez, Iván Del Moral, Yasmeen, Anila, Diaz, Marilyn, Aldon, Yoann, Bijl, Tom P L., Venkatayogi, Sravani, Martin Beem, Joshua S., Newman, Amanda, Jiang, Chuancang, Lee, Wen-Hsin, Pater, Maarten, Burger, Judith A., van Breemen, Mariëlle J., de Taeye, Steven W., Rantalainen, Kimmo, LaBranche, Celia, Saunders, Kevin O., Montefiori, David, Ozorowski, Gabriel, Ward, Andrew B., Crispin, Max, Moore, John P., Klasse, Per Johan, Haynes, Barton F., Wilson, Ian A., Wiehe, Kevin, Verkoczy, Laurent and Sanders, Rogier W. (2023) Germline-targeting HIV-1 Env vaccination induces VRC01-class antibodies with rare insertions. Cell Reports Medicine, 4 (4), 101003, [101003]. (doi:10.1016/j.xcrm.2023.101003).

Record type: Article

Abstract

Targeting germline (gl-) precursors of broadly neutralizing antibodies (bNAbs) is acknowledged as an important strategy for HIV-1 vaccines. The VRC01-class of bNAbs is attractive because of its distinct genetic signature. However, VRC01-class bNAbs often require extensive somatic hypermutation, including rare insertions and deletions. We describe a BG505 SOSIP trimer, termed GT1.2, to optimize binding to gl-CH31, the unmutated common precursor of the CH30-34 bNAb lineage that acquired a large CDRH1 insertion. The GT1.2 trimer activates gl-CH31 naive B cells in knock-in mice, and B cell responses could be matured by selected boosting immunogens to generate cross-reactive Ab responses. Next-generation B cell sequencing reveals selection for VRC01-class mutations, including insertions in CDRH1 and FWR3 at positions identical to VRC01-class bNAbs, as well as CDRL1 deletions and/or glycine substitutions to accommodate the N276 glycan. These results provide proof of concept for vaccine-induced affinity maturation of B cell lineages that require rare insertions and deletions.

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Published date: 18 April 2023
Additional Information: Funding Information: We are grateful to the staff of Advanced Photon Source BL 23-IDD for assistance. GM/CA@APS has been funded by the National Cancer Institute ( ACB-12002 ) and the National Institute of General Medical Sciences ( AGM-12006 , P30GM138396 ). This research used resources of the Advanced Photon Sciences under contract no. DE-AC02-06CH11357 . This work is supported by the Netherlands Organisation for Scientific Research (N.W.O.) Vici grant (R.W.S.); Bill & Melinda Gates Foundation , Collaboration for AIDS Vaccine Discovery (C.A.V.D.) grants INV-002022 (R.W.S.) and OPP1115782 / INV-002916 (A.B.W.); Fondation Dormeur, Vaduz (R.W.S.); and grants from the NIAID , Division of AIDS , NIH UM1 grants for the Duke Center for HIV/AIDS Vaccine Immunology-Immunogen Discovery (CHAVI-ID; UM1530AI100645 and Consortia for HIV/AIDS Vaccine Development [ CHAVD ]) UM1AI144371 to B.F.H. and R01 grant AI087202 (L.K.V.). P.J.K. and J.P.M. are supported by R01 AI036082 and A.B.W., I.A.W., R.W.S., P.J.K., and J.P.M. are supported by a HIVRAD P01 AI110657 grant. M.C. is funded by the International AIDS Vaccine Initiative (IAVI) through grant INV-008352 and the Bill & Melinda Gates Foundation OPP1153692 . Funding for the neutralization assays was provided by NIH / NIAID contract #HHSN272201800004C . Funding Information: We are grateful to the staff of Advanced Photon Source BL 23-IDD for assistance. GM/CA@APS has been funded by the National Cancer Institute (ACB-12002) and the National Institute of General Medical Sciences (AGM-12006, P30GM138396). This research used resources of the Advanced Photon Sciences under contract no. DE-AC02-06CH11357. This work is supported by the Netherlands Organisation for Scientific Research (N.W.O.) Vici grant (R.W.S.); Bill & Melinda Gates Foundation, Collaboration for AIDS Vaccine Discovery (C.A.V.D.) grants INV-002022 (R.W.S.) and OPP1115782/INV-002916 (A.B.W.); Fondation Dormeur, Vaduz (R.W.S.); and grants from the NIAID, Division of AIDS, NIH UM1 grants for the Duke Center for HIV/AIDS Vaccine Immunology-Immunogen Discovery (CHAVI-ID; UM1530AI100645 and Consortia for HIV/AIDS Vaccine Development [CHAVD]) UM1AI144371 to B.F.H. and R01 grant AI087202 (L.K.V.). P.J.K. and J.P.M. are supported by R01 AI036082 and A.B.W. I.A.W. R.W.S. P.J.K. and J.P.M. are supported by a HIVRAD P01 AI110657 grant. M.C. is funded by the International AIDS Vaccine Initiative (IAVI) through grant INV-008352 and the Bill & Melinda Gates Foundation OPP1153692. Funding for the neutralization assays was provided by NIH/NIAID contract #HHSN272201800004C. Conceptualization: M.M.-R. R.D. B.F.H. L.W. L.K.V. and R.W.S.; investigation: T.G.C. M.M.-R. J.Z. A.S. A.S.K. A.L. R.D. J.A. J.L.S. J.C.P. I.d.M.S. A.Y. M.D. Y.A. T.P.L.B. S.V. J.M.B. A.N. C.J. W.-H.L. M.P. J.A.B. M.J.v.B. and P.J.K.; methodology: T.G.C. M.M.-R. J.Z. A.S. S.K. M.P. M.C. P.J.K. I.A.W. K.W. L.K.V. and R.W.S.; project administration: T.G.C. M.M.-R. K.W. L.K.V. and R.W.S.; supervision: C.L. D.M. G.O. A.B.W. M.C. J.P.M. P.J.K. B.F.H. I.A.W. K.W. L.K.V. and R.W.S.; writing – original draft: T.G.C. L.K.V. and R.W.S.; review and editing: all authors. Amsterdam UMC has filed a patent application related to germline-targeting HIV-1 Env trimers. Publisher Copyright: © 2023 The Author(s)
Keywords: HIV antibodies, HIV seropositivity, HIV-1/genetics, animals, antibodies, neutralizing, broadly neutralizing antibodies, mice, vaccination, insertions, mouse model, deletions, vaccines, neutralizing antibodies, bNAbs, germline-targeting, NGS, HIV-1 Env

Identifiers

Local EPrints ID: 477207
URI: http://eprints.soton.ac.uk/id/eprint/477207
ISSN: 2666-3791
PURE UUID: ec4dee9f-0341-45cd-902c-dd3c8c79cb3c
ORCID for Joel D. Allen: ORCID iD orcid.org/0000-0003-2547-968X
ORCID for Max Crispin: ORCID iD orcid.org/0000-0002-1072-2694

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Date deposited: 01 Jun 2023 16:39
Last modified: 17 Mar 2024 04:09

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Contributors

Author: Tom G. Caniels
Author: Max Medina-Ramírez
Author: Jinsong Zhang
Author: Anita Sarkar
Author: Sonu Kumar
Author: Alex LaBranche
Author: Ronald Derking
Author: Joel D. Allen ORCID iD
Author: Jonne L. Snitselaar
Author: Joan Capella-Pujol
Author: Iván Del Moral Sánchez
Author: Anila Yasmeen
Author: Marilyn Diaz
Author: Yoann Aldon
Author: Tom P L. Bijl
Author: Sravani Venkatayogi
Author: Joshua S. Martin Beem
Author: Amanda Newman
Author: Chuancang Jiang
Author: Wen-Hsin Lee
Author: Maarten Pater
Author: Judith A. Burger
Author: Mariëlle J. van Breemen
Author: Steven W. de Taeye
Author: Kimmo Rantalainen
Author: Celia LaBranche
Author: Kevin O. Saunders
Author: David Montefiori
Author: Gabriel Ozorowski
Author: Andrew B. Ward
Author: Max Crispin ORCID iD
Author: John P. Moore
Author: Per Johan Klasse
Author: Barton F. Haynes
Author: Ian A. Wilson
Author: Kevin Wiehe
Author: Laurent Verkoczy
Author: Rogier W. Sanders

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