Slow Delivery Immunization Enhances HIV Neutralizing Antibody and Germinal Center Responses via Modulation of Immunodominance
Name
nihms-1528121.pdf
Description
Accepted version
Size
3.42 MB
Format
Adobe PDF
Checksum (MD5)
ac954ce11d75ef8f0a7e101523aacf0a
Author(s)
Cirelli, Kimberly M.
Carnathan, Diane G.
Nogal, Bartek
Martin, Jacob T.
Rodriguez, Oscar L.
Upadhyay, Amit A.
Enemuo, Chiamaka A.
Gebru, Etse H.
Choe, Yury
Viviano, Federico
Date Issued
May 2019
Journal
Cell
Publisher
Elsevier BV
Citation
Cirelli, Kimberly M. "Slow Delivery Immunization Enhances HIV Neutralizing Antibody and Germinal Center Responses via Modulation of Immunodominance." Cell 177, 5 (May 2019): P1153-1171.e28 © 2019 Elsevier
Version
Author's final manuscript
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.
MIT Department
Massachusetts Institute of Technology. Department of Materials Science and Engineering
Koch Institute for Integrative Cancer Research at MIT
Terms of Use
Creative Commons Attribution-NonCommercial-NoDerivs License
Persistent DSpace Link
DOI of Published Version
https://doi.org/10.1016/j.cell.2019.04.012
