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

TitleSequential Immunization Elicits Broadly Neutralizing Anti-HIV-1 Antibodies in Ig Knockin Mice.
Publication TypeJournal Article
Year of Publication2016
AuthorsEscolano A, Steichen JM, Dosenovic P, Kulp DW, Golijanin J, Sok D, Freund NT, Gitlin AD, Oliveira T, Araki T, Lowe S, Chen ST, Heinemann J, Yao K-H, Georgeson E, Saye-Francisco KL, Gazumyan A, Adachi Y, Kubitz M, Burton DR, Schief WR, Nussenzweig MC
JournalCell
Volume166
Issue6
Pagination1445-1458.e12
Date Published09/08/2016
ISSN0092-8674
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.

DOI10.1016/j.cell.2016.07.030
Alternate JournalCell
PubMed ID27610569
PubMed Central IDPMC5019122
Grant ListP01 AI100148 / AI / NIAID NIH HHS / United States
U19 AI109632 / AI / NIAID NIH HHS / United States
/ / Howard Hughes Medical Institute / United States
UM1 AI100663 / AI / NIAID NIH HHS / United States
T32 GM007739 / GM / NIGMS NIH HHS / United States
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