Particulate Array of Well-Ordered HIV Clade C Env Trimers Elicits Neutralizing Antibodies that Display a Unique V2 Cap Approach

Paola Martinez-Murillo; Karen Tran; Javier Guenaga; Gustaf Lindgren; Monika Àdori; Yu Feng; Ganesh E. Phad; Néstor Vázquez Bernat; Shridhar Bale; Jidnyasa Ingale; Viktoriya Dubrovskaya; Sijy O'Dell; Lotta Pramanik; Mats Spångberg; Martin Corcoran; Karin Loré; John R. Mascola; Richard T. Wyatt; Gunilla B. Karlsson Hedestam

doi:10.1016/j.immuni.2017.04.021

Particulate Array of Well-Ordered HIV Clade C Env Trimers Elicits Neutralizing Antibodies that Display a Unique V2 Cap Approach

Paola Martinez-Murillo, Karen Tran, Javier Guenaga, Gustaf Lindgren, Monika Àdori, Yu Feng, Ganesh E. Phad, Néstor Vázquez Bernat, Shridhar Bale, Jidnyasa Ingale, Viktoriya Dubrovskaya, Sijy O'Dell, Lotta Pramanik, Mats Spångberg, Martin Corcoran, Karin Loré, John R. Mascola, Richard T. Wyatt, Gunilla B. Karlsson Hedestam

Knight Cancer Institute

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

76 Scopus citations

Abstract

The development of soluble envelope glycoprotein (Env) mimetics displaying ordered trimeric symmetry has ushered in a new era in HIV-1 vaccination. The recently reported native, flexibly linked (NFL) design allows the generation of native-like trimers from clinical isolates at high yields and homogeneity. As the majority of infections world-wide are of the clade C subtype, we examined responses in non-human primates to well-ordered subtype C 16055 trimers administered in soluble or high-density liposomal formats. We detected superior germinal center formation and enhanced autologous neutralizing antibodies against the neutralization-resistant (tier 2) 16055 virus following inoculation of liposome-arrayed trimers. Epitope mapping of the neutralizing monoclonal antibodies (mAbs) indicated major contacts with the V2 apex, and 3D electron microscopy reconstructions of Fab-trimer complexes revealed a horizontal binding angle to the Env spike. These vaccine-elicited mAbs target the V2 cap, demonstrating a means to accomplish tier 2 virus neutralization by penetrating the dense N-glycan shield.

Original language	English (US)
Pages (from-to)	804-817.e7
Journal	Immunity
Volume	46
Issue number	5
DOIs	https://doi.org/10.1016/j.immuni.2017.04.021
State	Published - May 16 2017

Keywords

B cell responses
HIV-1
clade C
envelope glycoproteins
epitope
germinal centers
liposome
monoclonal antibody
trimers
vaccine

ASJC Scopus subject areas

Immunology and Allergy
Immunology
Infectious Diseases

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10.1016/j.immuni.2017.04.021

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Martinez-Murillo, P., Tran, K., Guenaga, J., Lindgren, G., Àdori, M., Feng, Y., Phad, G. E., Vázquez Bernat, N., Bale, S., Ingale, J., Dubrovskaya, V., O'Dell, S., Pramanik, L., Spångberg, M., Corcoran, M., Loré, K., Mascola, J. R., Wyatt, R. T., & Karlsson Hedestam, G. B. (2017). Particulate Array of Well-Ordered HIV Clade C Env Trimers Elicits Neutralizing Antibodies that Display a Unique V2 Cap Approach. Immunity, 46(5), 804-817.e7. https://doi.org/10.1016/j.immuni.2017.04.021

Martinez-Murillo, P, Tran, K, Guenaga, J, Lindgren, G, Àdori, M, Feng, Y, Phad, GE, Vázquez Bernat, N, Bale, S, Ingale, J, Dubrovskaya, V, O'Dell, S, Pramanik, L, Spångberg, M, Corcoran, M, Loré, K, Mascola, JR, Wyatt, RT & Karlsson Hedestam, GB 2017, 'Particulate Array of Well-Ordered HIV Clade C Env Trimers Elicits Neutralizing Antibodies that Display a Unique V2 Cap Approach', Immunity, vol. 46, no. 5, pp. 804-817.e7. https://doi.org/10.1016/j.immuni.2017.04.021

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abstract = "The development of soluble envelope glycoprotein (Env) mimetics displaying ordered trimeric symmetry has ushered in a new era in HIV-1 vaccination. The recently reported native, flexibly linked (NFL) design allows the generation of native-like trimers from clinical isolates at high yields and homogeneity. As the majority of infections world-wide are of the clade C subtype, we examined responses in non-human primates to well-ordered subtype C 16055 trimers administered in soluble or high-density liposomal formats. We detected superior germinal center formation and enhanced autologous neutralizing antibodies against the neutralization-resistant (tier 2) 16055 virus following inoculation of liposome-arrayed trimers. Epitope mapping of the neutralizing monoclonal antibodies (mAbs) indicated major contacts with the V2 apex, and 3D electron microscopy reconstructions of Fab-trimer complexes revealed a horizontal binding angle to the Env spike. These vaccine-elicited mAbs target the V2 cap, demonstrating a means to accomplish tier 2 virus neutralization by penetrating the dense N-glycan shield.",

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AU - Tran, Karen

AU - Guenaga, Javier

AU - Lindgren, Gustaf

AU - Àdori, Monika

AU - Feng, Yu

AU - Phad, Ganesh E.

AU - Vázquez Bernat, Néstor

AU - Bale, Shridhar

AU - Ingale, Jidnyasa

AU - Dubrovskaya, Viktoriya

AU - O'Dell, Sijy

AU - Pramanik, Lotta

AU - Spångberg, Mats

AU - Corcoran, Martin

AU - Loré, Karin

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AU - Karlsson Hedestam, Gunilla B.

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N2 - The development of soluble envelope glycoprotein (Env) mimetics displaying ordered trimeric symmetry has ushered in a new era in HIV-1 vaccination. The recently reported native, flexibly linked (NFL) design allows the generation of native-like trimers from clinical isolates at high yields and homogeneity. As the majority of infections world-wide are of the clade C subtype, we examined responses in non-human primates to well-ordered subtype C 16055 trimers administered in soluble or high-density liposomal formats. We detected superior germinal center formation and enhanced autologous neutralizing antibodies against the neutralization-resistant (tier 2) 16055 virus following inoculation of liposome-arrayed trimers. Epitope mapping of the neutralizing monoclonal antibodies (mAbs) indicated major contacts with the V2 apex, and 3D electron microscopy reconstructions of Fab-trimer complexes revealed a horizontal binding angle to the Env spike. These vaccine-elicited mAbs target the V2 cap, demonstrating a means to accomplish tier 2 virus neutralization by penetrating the dense N-glycan shield.

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Particulate Array of Well-Ordered HIV Clade C Env Trimers Elicits Neutralizing Antibodies that Display a Unique V2 Cap Approach

Abstract

Keywords

ASJC Scopus subject areas

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