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

Authors: Cirelli, Kimberly M and Carnathan, Diane G and Nogal, Bartek and Martin, Jacob T and Rodriguez, Oscar L and Upadhyay, Amit A and Enemuo, Chiamaka A and Gebru, Etse H and Choe, Yury and Viviano, Federico and Nakao, Catherine and Pauthner, Matthias G and Reiss, Samantha and Cottrell, Christopher A and Smith, Melissa L and Bastidas, Raiza and Gibson, William and Wolabaugh, Amber N and Melo, Mariane B and Cossette, Benjamin and Kumar, Venkatesh and Patel, Nirav B and Tokatlian, Talar and Menis, Sergey and Kulp, Daniel W and Burton, Dennis R and Murrell, Ben and Schief, William R and Bosinger, Steven E and Ward, Andrew B and Watson, Corey T and Silvestri, Guido and Irvine, Darrell J and Crotty, Shane

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. Copyright © 2019 Elsevier Inc. All rights reserved.

Journal: Cell
DOI: 10.1016/j.cell.2019.04.012
Year: 2019

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