Slow Delivery Immunization Enhances HIV Neutralizing Antibody and Germinal Center Responses via Modulation of Immunodominance
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 f...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier BV
2020
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| Online Access: | https://hdl.handle.net/1721.1/125926 |
| _version_ | 1826215892487241728 |
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| author | 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 Nakao, Catherine Pauthner, Matthias G. Reiss, Samantha Cottrell, Christopher A. Smith, Melissa L. Bastidas, Raiza Gibson, William Wolabaugh, Amber N. Melo, Mariane Bandeira Cossette, Benjamin Kumar, Venkatesh Patel, Nirav B. Tokatlian, Talar Menis, Sergey Kulp, Daniel W. Burton, Dennis R. Murrell, Ben Schief, William R. Bosinger, Steven E. Ward, Andrew B. Watson, Corey T. Silvestri, Guido Irvine, Darrell J Crotty, Shane |
| author2 | Massachusetts Institute of Technology. Department of Materials Science and Engineering |
| author_facet | Massachusetts Institute of Technology. Department of Materials Science and Engineering 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 Nakao, Catherine Pauthner, Matthias G. Reiss, Samantha Cottrell, Christopher A. Smith, Melissa L. Bastidas, Raiza Gibson, William Wolabaugh, Amber N. Melo, Mariane Bandeira Cossette, Benjamin Kumar, Venkatesh Patel, Nirav B. Tokatlian, Talar Menis, Sergey Kulp, Daniel W. Burton, Dennis R. Murrell, Ben Schief, William R. Bosinger, Steven E. Ward, Andrew B. Watson, Corey T. Silvestri, Guido Irvine, Darrell J Crotty, Shane |
| author_sort | Cirelli, Kimberly M. |
| collection | MIT |
| description | 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. |
| first_indexed | 2024-09-23T16:38:42Z |
| format | Article |
| id | mit-1721.1/125926 |
| institution | Massachusetts Institute of Technology |
| language | English |
| last_indexed | 2024-09-23T16:38:42Z |
| publishDate | 2020 |
| publisher | Elsevier BV |
| record_format | dspace |
| spelling | mit-1721.1/1259262022-10-03T07:22:44Z Slow Delivery Immunization Enhances HIV Neutralizing Antibody and Germinal Center Responses via Modulation of Immunodominance 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 Nakao, Catherine Pauthner, Matthias G. Reiss, Samantha Cottrell, Christopher A. Smith, Melissa L. Bastidas, Raiza Gibson, William Wolabaugh, Amber N. Melo, Mariane Bandeira Cossette, Benjamin Kumar, Venkatesh Patel, Nirav B. Tokatlian, Talar Menis, Sergey Kulp, Daniel W. Burton, Dennis R. Murrell, Ben Schief, William R. Bosinger, Steven E. Ward, Andrew B. Watson, Corey T. Silvestri, Guido Irvine, Darrell J Crotty, Shane Massachusetts Institute of Technology. Department of Materials Science and Engineering Koch Institute for Integrative Cancer Research at MIT 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. National Institutes of Health (Grant AI125068) National Institutes of Health (Grant Al100663) 2020-06-22T20:38:39Z 2020-06-22T20:38:39Z 2019-05 2019-02 2020-06-19T16:51:11Z Article http://purl.org/eprint/type/JournalArticle 0092-8674 https://hdl.handle.net/1721.1/125926 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 en http://dx.doi.org/10.1016/j.cell.2019.04.012 Cell Creative Commons Attribution-NonCommercial-NoDerivs License http://creativecommons.org/licenses/by-nc-nd/4.0/ application/pdf Elsevier BV PMC |
| spellingShingle | 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 Nakao, Catherine Pauthner, Matthias G. Reiss, Samantha Cottrell, Christopher A. Smith, Melissa L. Bastidas, Raiza Gibson, William Wolabaugh, Amber N. Melo, Mariane Bandeira Cossette, Benjamin Kumar, Venkatesh Patel, Nirav B. Tokatlian, Talar Menis, Sergey Kulp, Daniel W. Burton, Dennis R. Murrell, Ben Schief, William R. Bosinger, Steven E. Ward, Andrew B. Watson, Corey T. Silvestri, Guido Irvine, Darrell J Crotty, Shane Slow Delivery Immunization Enhances HIV Neutralizing Antibody and Germinal Center Responses via Modulation of Immunodominance |
| title | Slow Delivery Immunization Enhances HIV Neutralizing Antibody and Germinal Center Responses via Modulation of Immunodominance |
| title_full | Slow Delivery Immunization Enhances HIV Neutralizing Antibody and Germinal Center Responses via Modulation of Immunodominance |
| title_fullStr | Slow Delivery Immunization Enhances HIV Neutralizing Antibody and Germinal Center Responses via Modulation of Immunodominance |
| title_full_unstemmed | Slow Delivery Immunization Enhances HIV Neutralizing Antibody and Germinal Center Responses via Modulation of Immunodominance |
| title_short | Slow Delivery Immunization Enhances HIV Neutralizing Antibody and Germinal Center Responses via Modulation of Immunodominance |
| title_sort | slow delivery immunization enhances hiv neutralizing antibody and germinal center responses via modulation of immunodominance |
| url | https://hdl.handle.net/1721.1/125926 |
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