Sequential Immunization Elicits Broadly Neutralizing Anti-HIV-1 Antibodies in Ig Knockin Mice

Amelia Escolano, Jon M. Steichen, Pia Dosenovic, Daniel W. Kulp, Jovana Golijanin, Devin Sok, Natalia T. Freund, Alexander D. Gitlin, Thiago Oliveira, Tatsuya Araki, Sarina Lowe, Spencer T. Chen, Jennifer Heinemann, Kai Hui Yao, Erik Georgeson, Karen L. Saye-Francisco, Anna Gazumyan, Yumiko Adachi, Michael Kubitz, Dennis R. BurtonWilliam R. Schief*, Michel C. Nussenzweig

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

235 Scopus citations

Abstract

A vaccine that elicits broadly neutralizing antibodies (bNAbs) against HIV-1 is likely to be protective, but this has not been achieved. To explore immunization regimens that might elicit bNAbs, we produced and immunized mice expressing the predicted germline PGT121, a bNAb specific for the V3-loop and surrounding glycans on the HIV-1 spike. Priming with an epitope-modified immunogen designed to activate germline antibody-expressing B cells, followed by ELISA-guided boosting with a sequence of directional immunogens, native-like trimers with decreasing epitope modification, elicited heterologous tier-2-neutralizing responses. In contrast, repeated immunization with the priming immunogen did not. Antibody cloning confirmed elicitation of high levels of somatic mutation and tier-2-neutralizing antibodies resembling the authentic human bNAb. Our data establish that sequential immunization with specifically designed immunogens can induce high levels of somatic mutation and shepherd antibody maturation to produce bNAbs from their inferred germline precursors.

Original languageEnglish
Pages (from-to)1445-1458.e12
JournalCell
Volume166
Issue number6
DOIs
StatePublished - 8 Sep 2016
Externally publishedYes

Funding

FundersFunder number
CAVD
Collaboration for AIDS VaccineOPP1124068, OPP1033115
IAVI NAC Center
International AIDS Vaccine Initiative Neutralizing Antibody Consortium and Center
MSTPT32GM07739
PCTI-FICYT
National Institutes of Health1UM1 AI100663
National Institute of Allergy and Infectious DiseasesAI100148, R01AI113867, AI109632
Rockefeller University
Ragon Institute of MGH, MIT and Harvard
Robertson Foundation
Vetenskapsrådet

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