Slow Delivery Immunization Enhances HIV Neutralizing Antibody and Germinal Center Responses via Modulation of Immunodominance

• Type of Material: Article
• Authors: Kimberly M. Cirelli, La Jolla Institute for Allergy and Immunology; Diane G. Carnathan, Scripps Research Institute; Bartek Nogal, Scripps Research Institute; Jacob T. Martin, Scripps Research Institute; Oscar L. Rodriguez, Icahn School of Medicine at Mount Sinai; Amit Upadhyay, Emory University; Chiamaka A. Enemuo, Emory University; Etse H. Gebru, Emory University; Yury Choe, Emory University; Federico Viviano, Emory University; Catherine Nakao, La Jolla Institute for Allergy and Immunology; Matthias G. Pauthner, Scripps Research Institute; Samantha Reiss, La Jolla Institute for Allergy and Immunology; Christopher A. Cottrell, Scripps Research Institute; Melissa L. Smith, Icahn School of Medicine at Mount Sinai; Raiza Bastidas, Scripps Research Institute; William Gibson, University of Louisville; Amber N. Wolabaugh, Emory University; Mariane B. Melo, Scripps Research Institute; Benjamin Cossette, Massachusetts Institute of Technology; Venkatesh Kumar, University of California San Diego; Nirav B. Patel, Yerkes National Primate Research Center; Talar Tokatlian, Scripps Research Institute; Sergey Menis, Scripps Research Institute; Daniel W. Kulp, Scripps Research Institute; Dennis R. Burton, Scripps Research Institute; Ben Murrell, University of California San Diego; William R. Schief, Scripps Research Institute; Steven Bosinger, Emory University; Andrew B. Ward, Scripps Research Institute; Corey T. Watson, University of Louisville; Guido Silvestri, Emory University; Darrell J. Irvine, Scripps Research Institute; Shane Crotty, La Jolla Institute for Allergy and Immunology
• Language: English
• Date: 2019-05-16
• Publisher: Cell Press
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2019 Elsevier Inc.
• License: Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1016/j.cell.2019.04.012
• Title of Journal or Parent Work: Cell
• Volume: 177
• Issue: 5
• Start Page: 1153
• End Page: +
• Grant/Funding Information: This study was funded by the National Institutes of Health grants AI125068 (D.J.I., S.C.), Al100663 (Scripps CHAVI-ID: S.C., G.S., D.J.I., W.S., A.B.W., D.R.B.), RR00165/OD011132 (YNPRC), AI124436 (S.C., G.S., S.B.), AI136621 (A.B.W.), F31Al131873 (C.A.C.), and by the Ragon Institute and Howard Hughes Medical Institute (D.J.I).
• Keywords: Cryo-em structure; Biochemistry & Molecular Biology; Performance status; RNA-SEQ; Nonhuman primates; Follicular helper-cells; Cell Biology; Micro-needles; Antigen; Life Sciences & Biomedicine; Multiple sequence alignment; Vaccine; Science & Technology; Microscopy
• Research Categories: Biology, Cell; Health Sciences, Immunology; Biology, Molecular; Chemistry, Biochemistry

Abstract

Conventional immunization strategies will likely be insufficient for the development of a broadly neutralizing antibody (bnAb) vaccine for HIV or other difficult pathogens because of the immunological hurdles posed, including B cell immunodominance and germinal center (GC) quantity and quality. We found that two independent methods of slow delivery immunization of rhesus monkeys (RMs) resulted in more robust T follicular helper (TFH) cell responses and GC B cells with improved Env-binding, tracked by longitudinal fine needle aspirates. Improved GCs correlated with the development of >20-fold higher titers of autologous nAbs. Using a new RM genomic immunoglobulin locus reference, we identified differential IgV gene use between immunization modalities. Ab mapping demonstrated targeting of immunodominant non-neutralizing epitopes by conventional bolus-immunized animals, whereas slow delivery-immunized animals targeted a more diverse set of epitopes. Thus, alternative immunization strategies can enhance nAb development by altering GCs and modulating the immunodominance of non-neutralizing epitopes. An integrated immunological, bioinformatic and imaging approach demonstrates how slow delivery immunization enhances neutralizing antibody and germinal center reactions over conventional strategies in response to HIV Env protein immunization in non-human primates.