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

• Published in: Cell reports (Cambridge) Vol. 17; no. 9; pp. 2195 - 2209
• Main Authors: Havenar-Daughton, Colin, Carnathan, Diane G., Torrents de la Peña, Alba, Pauthner, Matthias, Briney, Bryan, Reiss, Samantha M., Wood, Jennifer S., Kaushik, Kirti, van Gils, Marit J., Rosales, Sandy L., van der Woude, Patricia, Locci, Michela, Le, Khoa M., de Taeye, Steven W., Sok, Devin, Mohammed, Ata Ur Rasheed, Huang, Jessica, Gumber, Sanjeev, Garcia, AnaPatricia, Kasturi, Sudhir P., Pulendran, Bali, Moore, John P., Ahmed, Rafi, Seumois, Grégory, Burton, Dennis R., Sanders, Rogier W., Silvestri, Guido, Crotty, Shane
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 22.11.2016
• Subjects: Animals; Antibodies, Neutralizing - immunology; Antibody Formation - immunology; B-Lymphocytes - immunology; Biopsy, Fine-Needle; Cell Lineage; Clone Cells; env Gene Products, Human Immunodeficiency Virus - immunology; Germinal Center - immunology; HIV-1 - immunology; Immunization; Macaca mulatta; Protein Binding; Protein Multimerization; T-Lymphocytes, Helper-Inducer - immunology; vaccines; vaccines
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2016.10.085

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. [Display omitted] •Fine needle aspirates quantitatively monitor germinal center activity in lymph nodes•Neutralizing antibodies correlate with GC B cell magnitude, not ELISA Ab titers•Tfh cell quality is associated with vaccine-elicited HIV-neutralizing antibodies•LN FNA probing of GCs should be an immune correlate in HIV vaccine trials This study explores the immunological process by which a protein vaccine elicits HIV-neutralizing antibodies. Using direct probing of lymph nodes, Havenar-Daughton et al. show that neutralizing antibody development correlates with germinal center B cell frequencies and Tfh cells and that those responses can be tracked by LN FNAs over time.