Virus-like Particles Identify an HIV V1V2 Apex-Binding Neutralizing Antibody that Lacks a Protruding Loop

Evan M. Cale; Jason Gorman; Nathan A. Radakovich; Ema T. Crooks; Keiko Osawa; Tommy Tong; Jiaqi Li; Raju Nagarajan; Gabriel Ozorowski; David R. Ambrozak; Mangai Asokan; Robert T. Bailer; Anthony K. Bennici; Xuejun Chen; Nicole A. Doria-Rose; Aliaksandr Druz; Yu Feng; M. Gordon Joyce; Mark K. Louder; Sijy O'Dell; Courtney Oliver; Marie Pancera; Mark Connors; Thomas J. Hope; Thomas B. Kepler; Richard T. Wyatt; Andrew B. Ward; Ivelin S. Georgiev; Peter D. Kwong; John R. Mascola; James M. Binley

doi:10.1016/j.immuni.2017.04.011

Virus-like Particles Identify an HIV V1V2 Apex-Binding Neutralizing Antibody that Lacks a Protruding Loop

Evan M. Cale, Jason Gorman, Nathan A. Radakovich, Ema T. Crooks, Keiko Osawa, Tommy Tong, Jiaqi Li, Raju Nagarajan, Gabriel Ozorowski, David R. Ambrozak, Mangai Asokan, Robert T. Bailer, Anthony K. Bennici, Xuejun Chen, Nicole A. Doria-Rose, Aliaksandr Druz, Yu Feng, M. Gordon Joyce, Mark K. Louder, Sijy O'DellCourtney Oliver, Marie Pancera, Mark Connors, Thomas J. Hope, Thomas B. Kepler, Richard T. Wyatt, Andrew B. Ward, Ivelin S. Georgiev, Peter D. Kwong^*, John R. Mascola, James M. Binley

^*Corresponding author for this work

Cell & Developmental Biology

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

67 Scopus citations

Abstract

Most HIV-1-specific neutralizing antibodies isolated to date exhibit unusual characteristics that complicate their elicitation. Neutralizing antibodies that target the V1V2 apex of the HIV-1 envelope (Env) trimer feature unusually long protruding loops, which enable them to penetrate the HIV-1 glycan shield. As antibodies with loops of requisite length are created through uncommon recombination events, an alternative mode of apex binding has been sought. Here, we isolated a lineage of Env apex-directed neutralizing antibodies, N90-VRC38.01-11, by using virus-like particles and conformationally stabilized Env trimers as B cell probes. A crystal structure of N90-VRC38.01 with a scaffolded V1V2 revealed a binding mode involving side-chain-to-side-chain interactions that reduced the distance the antibody loop must traverse the glycan shield, thereby facilitating V1V2 binding via a non-protruding loop. The N90-VRC38 lineage thus identifies a solution for V1V2-apex binding that provides a more conventional B cell pathway for vaccine design.

Original language	English (US)
Pages (from-to)	777-791.e10
Journal	Immunity
Volume	46
Issue number	5
DOIs	https://doi.org/10.1016/j.immuni.2017.04.011
State	Published - May 16 2017

Funding

This work was supported by NIH grants RO1AI00790, RO1AI93278, and R33AI84714 (J.M.B.) U19AI117892-02 (T.B.K.), and by the intramural research program of the Vaccine Research Center, NIAID, NIH. We thank Bob Whalen (Altravax) for Rev and SIV Gag plasmids, Yang Dai (Scripps Research Institute) for the pAV MLV Gag plasmid, David Montefiori (Duke University) for large cohort serum-virus neutralization data, and Jonathan Stuckey for assistance with figures. Use of sector 22 (Southeast Region Collaborative Access team) at the Advanced Photon Source was supported by the US Department of Energy, Basic Energy Sciences, Office of Science, under contract #W-31-109-Eng-38. We thank donor N90 for participating. We thank J. Baalwa, D. Ellenberger, F. Gao, B. Hahn, K. Hong, J. Kim, F. McCutchan, D. Montefiori, L. Morris, J. Overbaugh, E. Sanders-Buell, G. Shaw, R. Swanstrom, M. Thomson, S. Tovanabutra, C. Williamson, and L. Zhang for contributing the HIV-1 Envelope plasmids used in our neutralization panel.

Keywords

B cell ontogeny
CDRH3
HIV
NAb
V1V2
VLP
antibody
bnAb
glycan shield
neutralization
trimer
vaccine-design template

ASJC Scopus subject areas

Immunology and Allergy
Immunology
Infectious Diseases

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1016/j.immuni.2017.04.011

Cite this

Cale, E. M., Gorman, J., Radakovich, N. A., Crooks, E. T., Osawa, K., Tong, T., Li, J., Nagarajan, R., Ozorowski, G., Ambrozak, D. R., Asokan, M., Bailer, R. T., Bennici, A. K., Chen, X., Doria-Rose, N. A., Druz, A., Feng, Y., Joyce, M. G., Louder, M. K., ... Binley, J. M. (2017). Virus-like Particles Identify an HIV V1V2 Apex-Binding Neutralizing Antibody that Lacks a Protruding Loop. Immunity, 46(5), 777-791.e10. https://doi.org/10.1016/j.immuni.2017.04.011

@article{2655672bea25435da43806843533d3fb,

title = "Virus-like Particles Identify an HIV V1V2 Apex-Binding Neutralizing Antibody that Lacks a Protruding Loop",

abstract = "Most HIV-1-specific neutralizing antibodies isolated to date exhibit unusual characteristics that complicate their elicitation. Neutralizing antibodies that target the V1V2 apex of the HIV-1 envelope (Env) trimer feature unusually long protruding loops, which enable them to penetrate the HIV-1 glycan shield. As antibodies with loops of requisite length are created through uncommon recombination events, an alternative mode of apex binding has been sought. Here, we isolated a lineage of Env apex-directed neutralizing antibodies, N90-VRC38.01-11, by using virus-like particles and conformationally stabilized Env trimers as B cell probes. A crystal structure of N90-VRC38.01 with a scaffolded V1V2 revealed a binding mode involving side-chain-to-side-chain interactions that reduced the distance the antibody loop must traverse the glycan shield, thereby facilitating V1V2 binding via a non-protruding loop. The N90-VRC38 lineage thus identifies a solution for V1V2-apex binding that provides a more conventional B cell pathway for vaccine design.",

keywords = "B cell ontogeny, CDRH3, HIV, NAb, V1V2, VLP, antibody, bnAb, glycan shield, neutralization, trimer, vaccine-design template",

author = "Cale, {Evan M.} and Jason Gorman and Radakovich, {Nathan A.} and Crooks, {Ema T.} and Keiko Osawa and Tommy Tong and Jiaqi Li and Raju Nagarajan and Gabriel Ozorowski and Ambrozak, {David R.} and Mangai Asokan and Bailer, {Robert T.} and Bennici, {Anthony K.} and Xuejun Chen and Doria-Rose, {Nicole A.} and Aliaksandr Druz and Yu Feng and Joyce, {M. Gordon} and Louder, {Mark K.} and Sijy O'Dell and Courtney Oliver and Marie Pancera and Mark Connors and Hope, {Thomas J.} and Kepler, {Thomas B.} and Wyatt, {Richard T.} and Ward, {Andrew B.} and Georgiev, {Ivelin S.} and Kwong, {Peter D.} and Mascola, {John R.} and Binley, {James M.}",

note = "Publisher Copyright: {\textcopyright} 2017 Elsevier Inc.",

year = "2017",

month = may,

day = "16",

doi = "10.1016/j.immuni.2017.04.011",

language = "English (US)",

volume = "46",

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Cale, EM, Gorman, J, Radakovich, NA, Crooks, ET, Osawa, K, Tong, T, Li, J, Nagarajan, R, Ozorowski, G, Ambrozak, DR, Asokan, M, Bailer, RT, Bennici, AK, Chen, X, Doria-Rose, NA, Druz, A, Feng, Y, Joyce, MG, Louder, MK, O'Dell, S, Oliver, C, Pancera, M, Connors, M, Hope, TJ, Kepler, TB, Wyatt, RT, Ward, AB, Georgiev, IS, Kwong, PD, Mascola, JR & Binley, JM 2017, 'Virus-like Particles Identify an HIV V1V2 Apex-Binding Neutralizing Antibody that Lacks a Protruding Loop', Immunity, vol. 46, no. 5, pp. 777-791.e10. https://doi.org/10.1016/j.immuni.2017.04.011

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T1 - Virus-like Particles Identify an HIV V1V2 Apex-Binding Neutralizing Antibody that Lacks a Protruding Loop

AU - Cale, Evan M.

AU - Gorman, Jason

AU - Radakovich, Nathan A.

AU - Crooks, Ema T.

AU - Osawa, Keiko

AU - Tong, Tommy

AU - Li, Jiaqi

AU - Nagarajan, Raju

AU - Ozorowski, Gabriel

AU - Ambrozak, David R.

AU - Asokan, Mangai

AU - Bailer, Robert T.

AU - Bennici, Anthony K.

AU - Chen, Xuejun

AU - Doria-Rose, Nicole A.

AU - Druz, Aliaksandr

AU - Feng, Yu

AU - Joyce, M. Gordon

AU - Louder, Mark K.

AU - O'Dell, Sijy

AU - Oliver, Courtney

AU - Pancera, Marie

AU - Connors, Mark

AU - Hope, Thomas J.

AU - Kepler, Thomas B.

AU - Wyatt, Richard T.

AU - Ward, Andrew B.

AU - Georgiev, Ivelin S.

AU - Kwong, Peter D.

AU - Mascola, John R.

AU - Binley, James M.

PY - 2017/5/16

Y1 - 2017/5/16

N2 - Most HIV-1-specific neutralizing antibodies isolated to date exhibit unusual characteristics that complicate their elicitation. Neutralizing antibodies that target the V1V2 apex of the HIV-1 envelope (Env) trimer feature unusually long protruding loops, which enable them to penetrate the HIV-1 glycan shield. As antibodies with loops of requisite length are created through uncommon recombination events, an alternative mode of apex binding has been sought. Here, we isolated a lineage of Env apex-directed neutralizing antibodies, N90-VRC38.01-11, by using virus-like particles and conformationally stabilized Env trimers as B cell probes. A crystal structure of N90-VRC38.01 with a scaffolded V1V2 revealed a binding mode involving side-chain-to-side-chain interactions that reduced the distance the antibody loop must traverse the glycan shield, thereby facilitating V1V2 binding via a non-protruding loop. The N90-VRC38 lineage thus identifies a solution for V1V2-apex binding that provides a more conventional B cell pathway for vaccine design.

AB - Most HIV-1-specific neutralizing antibodies isolated to date exhibit unusual characteristics that complicate their elicitation. Neutralizing antibodies that target the V1V2 apex of the HIV-1 envelope (Env) trimer feature unusually long protruding loops, which enable them to penetrate the HIV-1 glycan shield. As antibodies with loops of requisite length are created through uncommon recombination events, an alternative mode of apex binding has been sought. Here, we isolated a lineage of Env apex-directed neutralizing antibodies, N90-VRC38.01-11, by using virus-like particles and conformationally stabilized Env trimers as B cell probes. A crystal structure of N90-VRC38.01 with a scaffolded V1V2 revealed a binding mode involving side-chain-to-side-chain interactions that reduced the distance the antibody loop must traverse the glycan shield, thereby facilitating V1V2 binding via a non-protruding loop. The N90-VRC38 lineage thus identifies a solution for V1V2-apex binding that provides a more conventional B cell pathway for vaccine design.

KW - B cell ontogeny

KW - CDRH3

KW - HIV

KW - NAb

KW - V1V2

KW - VLP

KW - antibody

KW - bnAb

KW - glycan shield

KW - neutralization

KW - trimer

KW - vaccine-design template

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U2 - 10.1016/j.immuni.2017.04.011

DO - 10.1016/j.immuni.2017.04.011

M3 - Article

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AN - SCOPUS:85019399814

SN - 1074-7613

VL - 46

SP - 777-791.e10

JO - Immunity

JF - Immunity

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ER -

Virus-like Particles Identify an HIV V1V2 Apex-Binding Neutralizing Antibody that Lacks a Protruding Loop

Abstract

Funding

Keywords

ASJC Scopus subject areas

UN SDGs

Access to Document

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Crystal Structure of the Human Fab VRC38.01, an HIV-1 V1V2-Directed Neutralizing Antibody Isolated from Donor N90, bound to a scaffolded WITO V1V2 domain

Crystal Structure of the Human Fab VRC38.01, an HIV-1 V1V2-Directed Neutralizing Antibody Isolated from Donor N90

Cite this

Virus-like Particles Identify an HIV V1V2 Apex-Binding Neutralizing Antibody that Lacks a Protruding Loop

Abstract

Funding

Keywords

ASJC Scopus subject areas

UN SDGs

Access to Document

Other files and links

Fingerprint

Datasets

Crystal Structure of the Human Fab VRC38.01, an HIV-1 V1V2-Directed Neutralizing Antibody Isolated from Donor N90, bound to a scaffolded WITO V1V2 domain

Crystal Structure of the Human Fab VRC38.01, an HIV-1 V1V2-Directed Neutralizing Antibody Isolated from Donor N90

Cite this