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Author Notes:

Corresponding author. Correspondence: Email: shane@lji.org

CHD, GS, and SC designed the experiments. CHD, DGC, MP, SMR, JSW, KK, SR, KML, AURM, SG, AG, and SPK performed the experiments.

ATP, PW, SWT, MJG, and RWS contributed critical reagents. CHD and SC wrote the paper.

CHD, DGC, MP, BB, SMR, ML, BP, JPM, RA, DRB, RWS, GS, and SC analyzed the data and edited the paper.

We thank Francois Villinger for assistance with FNA pilot studies (University of Louisiana at Lafayette). We thank the Flow Cytometry Core at the La Jolla Institute for Allergy and Immunology for expert cell sorting assistance.

We thank Vijay Pandurangan (LJI), Jason Greenbaum, and Alex Fu of LJI bioinformatics for assistance with the RNA-seq analysis.

The authors declare no competing interests.

Subjects:

Research Funding:

This work was supported by the Scripps CHAVI-ID (SC, GS, DB, BP, RA) and National Primate Research Center funding (P51 RR000165/OD011132 to the Yerkes National Primate Research Center), with additional grants from NIAID (Emory Center for AIDS Research, NIH Grant # P30-AI-504, GS. HIVRAD, RWS, JPM), the Gates Foundation (CAVD BP, SC), and the European Research Council (ERC-StG-2011–280829-SHEV, RWS).

Keywords:

  • vaccines

Direct Probing of Germinal Center Responses Reveals Immunological Features and Bottlenecks for Neutralizing Antibody Responses to HIV Env Trimer

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Journal Title:

Cell Reports

Volume:

Volume 17, Number 9

Publisher:

, Pages 2195-2209

Type of Work:

Article | Final Publisher PDF

Abstract:

Generating tier 2 HIV-neutralizing antibody (nAb) responses by immunization remains a challenging problem, and the immunological barriers to induction of such responses with Env immunogens remain unclear. Here, some rhesus monkeys developed autologous tier 2 nAbs upon HIV Env trimer immunization (SOSIP.v5.2) whereas others did not. This was not because HIV Env trimers were immunologically silent because all monkeys made similar ELISA-binding antibody responses; the key difference was nAb versus non-nAb responses. We explored the immunological barriers to HIV nAb responses by combining a suite of techniques, including longitudinal lymph node fine needle aspirates. Unexpectedly, nAb development best correlated with booster immunization GC B cell magnitude and Tfh characteristics of the Env-specific CD4 T cells. Notably, these factors distinguished between successful and unsuccessful antibody responses because GC B cell frequencies and stoichiometry to GC Tfh cells correlated with nAb development, but did not correlate with total Env Ab binding titers.

Copyright information:

© 2016 The Author(s).

This is an Open Access work distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License (http://creativecommons.org/licenses/by-nc-nd/4.0/).

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