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

Research output: Contribution to journalArticle

36 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 languageEnglish (US)
Pages (from-to)804-817.e7
JournalImmunity
Volume46
Issue number5
DOIs
StatePublished - May 16 2017
Externally publishedYes

Keywords

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

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology
  • Infectious Diseases

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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