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

Colin Havenar-Daughton; Diane G Carnathan; Alba Torrents de la Peña; Matthias Pauthner; Bryan Briney; Samantha M Reiss; Jennifer S Wood; Kirti Kaushik; Marit J van Gils; Sandy L Rosales; Patricia van der Woude; Michela Locci; Khoa M Le; Steven W de Taeye; Devin Sok; Ata Ur Rasheed Mohammed; Jessica Huang; Sanjeev Gumber; AnaPatricia Garcia; Sudhir P Kasturi; Bali Pulendran; John P Moore; Rafi Ahmed; Grégory Seumois; Dennis R Burton; Rogier W Sanders; Guido Silvestri; Shane Crotty

doi:10.1016/j.celrep.2016.10.085

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

Cell Rep. 2016 Nov 22;17(9):2195-2209. doi: 10.1016/j.celrep.2016.10.085.

Authors

Colin Havenar-Daughton¹, Diane G Carnathan², Alba Torrents de la Peña³, Matthias Pauthner⁴, Bryan Briney⁴, Samantha M Reiss¹, Jennifer S Wood⁵, Kirti Kaushik¹, Marit J van Gils³, Sandy L Rosales⁶, Patricia van der Woude³, Michela Locci¹, Khoa M Le⁴, Steven W de Taeye³, Devin Sok⁴, Ata Ur Rasheed Mohammed⁷, Jessica Huang⁷, Sanjeev Gumber⁵, AnaPatricia Garcia⁵, Sudhir P Kasturi⁸, Bali Pulendran⁹, John P Moore¹⁰, Rafi Ahmed¹¹, Grégory Seumois⁶, Dennis R Burton¹², Rogier W Sanders¹³, Guido Silvestri⁹, Shane Crotty¹⁴

Affiliations

¹ Division of Vaccine Discovery, La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037, USA; Scripps Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery, La Jolla, CA 92037, USA.
² Scripps Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery, La Jolla, CA 92037, USA; Yerkes National Primate Research Center, Emory University, Atlanta, GA 30322, USA.
³ Department of Medical Microbiology, Academic Medical Center, University of Amsterdam, 1105 AZ Amsterdam, the Netherlands.
⁴ Scripps Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery, La Jolla, CA 92037, USA; Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, CA 92037, USA.
⁵ Yerkes National Primate Research Center, Emory University, Atlanta, GA 30322, USA.
⁶ Division of Vaccine Discovery, La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037, USA.
⁷ Emory Vaccine Center, Emory University School of Medicine, Atlanta, GA 30322, USA.
⁸ Yerkes National Primate Research Center, Emory University, Atlanta, GA 30322, USA; Emory Vaccine Center, Emory University School of Medicine, Atlanta, GA 30322, USA.
⁹ Scripps Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery, La Jolla, CA 92037, USA; Yerkes National Primate Research Center, Emory University, Atlanta, GA 30322, USA; Emory Vaccine Center, Emory University School of Medicine, Atlanta, GA 30322, USA.
¹⁰ Department of Microbiology and Immunology, Weill Medical College of Cornell University, New York, NY 10065, USA.
¹¹ Scripps Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery, La Jolla, CA 92037, USA; Emory Vaccine Center, Emory University School of Medicine, Atlanta, GA 30322, USA.
¹² Scripps Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery, La Jolla, CA 92037, USA; Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, CA 92037, USA; Ragon Institute of MGH, MIT, and Harvard, Cambridge, MA 02139, USA.
¹³ Department of Medical Microbiology, Academic Medical Center, University of Amsterdam, 1105 AZ Amsterdam, the Netherlands; Department of Microbiology and Immunology, Weill Medical College of Cornell University, New York, NY 10065, USA.
¹⁴ Division of Vaccine Discovery, La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037, USA; Scripps Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery, La Jolla, CA 92037, USA; Department of Medicine, Division of Infectious Diseases, University of California, San Diego, La Jolla, CA 92037, USA. Electronic address: shane@lji.org.

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.

Keywords: vaccines.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Antibodies, Neutralizing / immunology*
Antibody Formation / immunology*
B-Lymphocytes / immunology
Biopsy, Fine-Needle
Cell Lineage
Clone Cells
Germinal Center / immunology*
HIV-1 / immunology*
Immunization
Macaca mulatta
Protein Binding
Protein Multimerization*
T-Lymphocytes, Helper-Inducer / immunology
env Gene Products, Human Immunodeficiency Virus / immunology*

Substances

Antibodies, Neutralizing
env Gene Products, Human Immunodeficiency Virus

Abstract

Publication types

MeSH terms

Substances

Grants and funding