Identification of IOMA-class neutralizing antibodies targeting the CD4-binding site on the HIV-1 envelope glycoprotein

Jelle van Schooten; Elinaz Farokhi; Anna Schorcht; Tom L. G. M. van den Kerkhof; Hongmei Gao; Patricia van der Woude; Judith A. Burger; Tim G. Rijkhold Meesters; Tom Bijl; Riham Ghalaiyini; Hannah L. Turner; Jessica Dorning; Barbera D. C. van Schaik; Antoine H. C. van Kampen; Celia C. Labranche; Robyn L. Stanfield; Devin Sok; David C. Montefiori; Dennis R. Burton; Michael S. Seaman; Gabriel Ozorowski; Ian A. Wilson; Rogier W. Sanders; Andrew B. Ward; Marit J. van Gils

doi:https://doi.org/10.1038/s41467-022-32208-0

Identification of IOMA-class neutralizing antibodies targeting the CD4-binding site on the HIV-1 envelope glycoprotein

Jelle van Schooten, Elinaz Farokhi, Anna Schorcht, Tom L. G. M. van den Kerkhof, Hongmei Gao, Patricia van der Woude, Judith A. Burger, Tim G. Rijkhold Meesters, Tom Bijl, Riham Ghalaiyini, Hannah L. Turner, Jessica Dorning, Barbera D. C. van Schaik, Antoine H. C. van Kampen, Celia C. Labranche, Robyn L. Stanfield, Devin Sok, David C. Montefiori, Dennis R. Burton, Michael S. SeamanGabriel Ozorowski, Ian A. Wilson, Rogier W. Sanders, Andrew B. Ward, Marit J. van Gils

Research output: Contribution to journal › Article › Academic › peer-review

4 Citations (Scopus)

Abstract

A major goal of current HIV-1 vaccine design efforts is to induce broadly neutralizing antibodies (bNAbs). The VH1-2-derived bNAb IOMA directed to the CD4-binding site of the HIV-1 envelope glycoprotein is of interest because, unlike the better-known VH1-2-derived VRC01-class bNAbs, it does not require a rare short light chain complementarity-determining region 3 (CDRL3). Here, we describe three IOMA-class NAbs, ACS101-103, with up to 37% breadth, that share many characteristics with IOMA, including an average-length CDRL3. Cryo-electron microscopy revealed that ACS101 shares interactions with those observed with other VH1-2 and VH1-46-class bNAbs, but exhibits a unique binding mode to residues in loop D. Analysis of longitudinal sequences from the patient suggests that a transmitter/founder-virus lacking the N276 glycan might have initiated the development of these NAbs. Together these data strengthen the rationale for germline-targeting vaccination strategies to induce IOMA-class bNAbs and provide a wealth of sequence and structural information to support such strategies.

Original language	English
Article number	4515
Journal	Nature communications
Volume	13
Issue number	1
DOIs	https://doi.org/10.1038/s41467-022-32208-0
Publication status	Published - 1 Dec 2022

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van Schooten, J., Farokhi, E., Schorcht, A., van den Kerkhof, T. L. G. M., Gao, H., van der Woude, P., Burger, J. A., Meesters, T. G. R., Bijl, T., Ghalaiyini, R., Turner, H. L., Dorning, J., van Schaik, B. D. C., van Kampen, A. H. C., Labranche, C. C., Stanfield, R. L., Sok, D., Montefiori, D. C., Burton, D. R., ... van Gils, M. J. (2022). Identification of IOMA-class neutralizing antibodies targeting the CD4-binding site on the HIV-1 envelope glycoprotein. Nature communications, 13(1), Article 4515. https://doi.org/10.1038/s41467-022-32208-0

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title = "Identification of IOMA-class neutralizing antibodies targeting the CD4-binding site on the HIV-1 envelope glycoprotein",

abstract = "A major goal of current HIV-1 vaccine design efforts is to induce broadly neutralizing antibodies (bNAbs). The VH1-2-derived bNAb IOMA directed to the CD4-binding site of the HIV-1 envelope glycoprotein is of interest because, unlike the better-known VH1-2-derived VRC01-class bNAbs, it does not require a rare short light chain complementarity-determining region 3 (CDRL3). Here, we describe three IOMA-class NAbs, ACS101-103, with up to 37% breadth, that share many characteristics with IOMA, including an average-length CDRL3. Cryo-electron microscopy revealed that ACS101 shares interactions with those observed with other VH1-2 and VH1-46-class bNAbs, but exhibits a unique binding mode to residues in loop D. Analysis of longitudinal sequences from the patient suggests that a transmitter/founder-virus lacking the N276 glycan might have initiated the development of these NAbs. Together these data strengthen the rationale for germline-targeting vaccination strategies to induce IOMA-class bNAbs and provide a wealth of sequence and structural information to support such strategies.",

author = "{van Schooten}, Jelle and Elinaz Farokhi and Anna Schorcht and {van den Kerkhof}, {Tom L. G. M.} and Hongmei Gao and {van der Woude}, Patricia and Burger, {Judith A.} and Meesters, {Tim G. Rijkhold} and Tom Bijl and Riham Ghalaiyini and Turner, {Hannah L.} and Jessica Dorning and {van Schaik}, {Barbera D. C.} and {van Kampen}, {Antoine H. C.} and Labranche, {Celia C.} and Stanfield, {Robyn L.} and Devin Sok and Montefiori, {David C.} and Burton, {Dennis R.} and Seaman, {Michael S.} and Gabriel Ozorowski and Wilson, {Ian A.} and Sanders, {Rogier W.} and Ward, {Andrew B.} and {van Gils}, {Marit J.}",

note = "Funding Information: This work was supported by the HIV Vaccine Research and Design (HIVRAD) program (P01 AI110657 to A.B.W., R.W.S), the Bill and Melinda Gates Foundation CAVD (OPP1132237 to R.W.S., INV002022 to R.W.S. and OPP1146996 to M.S.S.), NIH/NIAID (HHSN272201800004C to D.C.M), and the European Union{\textquoteright}s Horizon 2020 research and innovation program under grant agreement no. 681137 (R.W.S.). R.W.S. is a recipient of a Vici fellowship from the Netherlands Organization for Scientific Research (NWO). J.v.S. is a recipient of a 2017 AMC Ph.D. Scholarship. This research used resources of the SSRL, SLAC National Accelerator Laboratory, which is supported by the U.S. Department of Energy, Office of Science, Office of Basic Energy Sciences under Contract No. DE-AC02-76SF00515. The SSRL Structural Molecular Biology Program is supported by the DOE Office of Biological and Environmental Research, and by the National Institutes of Health, National Institute of General Medical Sciences (including P41GM103393). Beamline 5.0.1 of the Advanced Light Source, a U.S. DOE Office of Science User Facility under Contract No. DE-AC02-05CH11231, is supported in part by the ALS-ENABLE program funded by the National Institutes of Health, National Institute of General Medical Sciences, grant P30 GM124169-01. Publisher Copyright: {\textcopyright} 2022, The Author(s).",

year = "2022",

month = dec,

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doi = "https://doi.org/10.1038/s41467-022-32208-0",

language = "English",

volume = "13",

journal = "Nature communications",

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van Schooten, J, Farokhi, E, Schorcht, A, van den Kerkhof, TLGM, Gao, H, van der Woude, P, Burger, JA, Meesters, TGR, Bijl, T, Ghalaiyini, R, Turner, HL, Dorning, J, van Schaik, BDC , van Kampen, AHC, Labranche, CC, Stanfield, RL, Sok, D, Montefiori, DC, Burton, DR, Seaman, MS, Ozorowski, G, Wilson, IA, Sanders, RW, Ward, AB & van Gils, MJ 2022, 'Identification of IOMA-class neutralizing antibodies targeting the CD4-binding site on the HIV-1 envelope glycoprotein', Nature communications, vol. 13, no. 1, 4515. https://doi.org/10.1038/s41467-022-32208-0

TY - JOUR

T1 - Identification of IOMA-class neutralizing antibodies targeting the CD4-binding site on the HIV-1 envelope glycoprotein

AU - van Schooten, Jelle

AU - Farokhi, Elinaz

AU - Schorcht, Anna

AU - van den Kerkhof, Tom L. G. M.

AU - Gao, Hongmei

AU - van der Woude, Patricia

AU - Burger, Judith A.

AU - Meesters, Tim G. Rijkhold

AU - Bijl, Tom

AU - Ghalaiyini, Riham

AU - Turner, Hannah L.

AU - Dorning, Jessica

AU - van Schaik, Barbera D. C.

AU - van Kampen, Antoine H. C.

AU - Labranche, Celia C.

AU - Stanfield, Robyn L.

AU - Sok, Devin

AU - Montefiori, David C.

AU - Burton, Dennis R.

AU - Seaman, Michael S.

AU - Ozorowski, Gabriel

AU - Wilson, Ian A.

AU - Sanders, Rogier W.

AU - Ward, Andrew B.

AU - van Gils, Marit J.

N1 - Funding Information: This work was supported by the HIV Vaccine Research and Design (HIVRAD) program (P01 AI110657 to A.B.W., R.W.S), the Bill and Melinda Gates Foundation CAVD (OPP1132237 to R.W.S., INV002022 to R.W.S. and OPP1146996 to M.S.S.), NIH/NIAID (HHSN272201800004C to D.C.M), and the European Union’s Horizon 2020 research and innovation program under grant agreement no. 681137 (R.W.S.). R.W.S. is a recipient of a Vici fellowship from the Netherlands Organization for Scientific Research (NWO). J.v.S. is a recipient of a 2017 AMC Ph.D. Scholarship. This research used resources of the SSRL, SLAC National Accelerator Laboratory, which is supported by the U.S. Department of Energy, Office of Science, Office of Basic Energy Sciences under Contract No. DE-AC02-76SF00515. The SSRL Structural Molecular Biology Program is supported by the DOE Office of Biological and Environmental Research, and by the National Institutes of Health, National Institute of General Medical Sciences (including P41GM103393). Beamline 5.0.1 of the Advanced Light Source, a U.S. DOE Office of Science User Facility under Contract No. DE-AC02-05CH11231, is supported in part by the ALS-ENABLE program funded by the National Institutes of Health, National Institute of General Medical Sciences, grant P30 GM124169-01. Publisher Copyright: © 2022, The Author(s).

PY - 2022/12/1

Y1 - 2022/12/1

N2 - A major goal of current HIV-1 vaccine design efforts is to induce broadly neutralizing antibodies (bNAbs). The VH1-2-derived bNAb IOMA directed to the CD4-binding site of the HIV-1 envelope glycoprotein is of interest because, unlike the better-known VH1-2-derived VRC01-class bNAbs, it does not require a rare short light chain complementarity-determining region 3 (CDRL3). Here, we describe three IOMA-class NAbs, ACS101-103, with up to 37% breadth, that share many characteristics with IOMA, including an average-length CDRL3. Cryo-electron microscopy revealed that ACS101 shares interactions with those observed with other VH1-2 and VH1-46-class bNAbs, but exhibits a unique binding mode to residues in loop D. Analysis of longitudinal sequences from the patient suggests that a transmitter/founder-virus lacking the N276 glycan might have initiated the development of these NAbs. Together these data strengthen the rationale for germline-targeting vaccination strategies to induce IOMA-class bNAbs and provide a wealth of sequence and structural information to support such strategies.

AB - A major goal of current HIV-1 vaccine design efforts is to induce broadly neutralizing antibodies (bNAbs). The VH1-2-derived bNAb IOMA directed to the CD4-binding site of the HIV-1 envelope glycoprotein is of interest because, unlike the better-known VH1-2-derived VRC01-class bNAbs, it does not require a rare short light chain complementarity-determining region 3 (CDRL3). Here, we describe three IOMA-class NAbs, ACS101-103, with up to 37% breadth, that share many characteristics with IOMA, including an average-length CDRL3. Cryo-electron microscopy revealed that ACS101 shares interactions with those observed with other VH1-2 and VH1-46-class bNAbs, but exhibits a unique binding mode to residues in loop D. Analysis of longitudinal sequences from the patient suggests that a transmitter/founder-virus lacking the N276 glycan might have initiated the development of these NAbs. Together these data strengthen the rationale for germline-targeting vaccination strategies to induce IOMA-class bNAbs and provide a wealth of sequence and structural information to support such strategies.

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U2 - https://doi.org/10.1038/s41467-022-32208-0

DO - https://doi.org/10.1038/s41467-022-32208-0

M3 - Article

C2 - 35922441

SN - 2041-1723

VL - 13

JO - Nature communications

JF - Nature communications

IS - 1

M1 - 4515

ER -

Identification of IOMA-class neutralizing antibodies targeting the CD4-binding site on the HIV-1 envelope glycoprotein

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