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

• Authors: Colin Havenar-Daughton, La Jolla Institute for Allergy and Immunology; Diane G. Carnathan, Scripps Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery; Alba Torrents de la Peña, University of Amsterdam; Matthias Pauthner, Scripps Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery; Bryan Briney, Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery; Samantha M. Reiss, La Jolla Institute for Allergy and Immunology; Jennifer S Wood, Emory University; Kirti Kaushik, La Jolla Institute for Allergy and Immunology; Marit J. van Gils, University of Amsterdam; Sandy Rosales, La Jolla Institute for Allergy and Immunology; Patricia van der Woude, University of Amsterdam; Michela Locci, La Jolla Institute for Allergy and Immunology; Khoa M. Le, Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery; Steven W. de Taeye, University of Amsterdam; Devin Sok, Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery; Ata Ur Rasheed Mohammed, Emory University School of Medicine; Jessica Huang, Emory University School of Medicine; Sanjeev Gumber, Emory University; Anapatricia Garcia, Emory University; Sudhir Kasturi, Emory University; Bali Pulendran, Emory University; John P. Moore, Weill Cornell Medical College; Rafi Ahmed, Emory University; Grégory Seumois, La Jolla Institute for Allergy and Immunology; Dennis R. Burton, Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery; Rogier W. Sanders, Academic Medical Centre, University of Amsterdam; Guido Silvestri, Emory University; Shane Crotty, La Jolla Institute for Allergy and Immunology
• Journal Title: Cell Reports
• Volume: Volume 17, Number 9
• Publisher: (publisher) | 2016-11-22, Pages 2195-2209
• Type of Work: Article | Final Publisher PDF
• Publisher DOI: http://doi.org/10.1016/j.celrep.2016.10.085
• Subjects: Health Sciences, Immunology; Health Sciences, General
• Keywords: vaccines

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.