Manipulating the Selection Forces during Affinity Maturation to Generate Cross-Reactive HIV Antibodies
Generation of potent antibodies by a mutation-selection process called affinity maturation is a key component of effective immune responses. Antibodies that protect against highly mutable pathogens must neutralize diverse strains. Developing effective immunization strategies to drive their evolution...
| Main Authors: | , , , , , , , , , , , , |
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| Format: | Article |
| Language: | en_US |
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Elsevier
2016
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| Online Access: | http://hdl.handle.net/1721.1/101768 https://orcid.org/0000-0003-2398-5896 https://orcid.org/0000-0002-6064-0531 https://orcid.org/0000-0003-1268-9602 https://orcid.org/0000-0002-1112-5912 |
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| author | Wang, Shenshen Mata-Fink, Jordi Kriegsman, Barry Irvine, Darrell J. Eisen, Herman N. Burton, Dennis R. Kardar, Mehran Chakraborty, Arup K. Wittrup, Karl Dane Eisen, Herman N. Hanson, Melissa Catherine Irvine, Darrell J Chakraborty, Arup K |
| author2 | Massachusetts Institute of Technology. Institute for Medical Engineering & Science |
| author_facet | Massachusetts Institute of Technology. Institute for Medical Engineering & Science Wang, Shenshen Mata-Fink, Jordi Kriegsman, Barry Irvine, Darrell J. Eisen, Herman N. Burton, Dennis R. Kardar, Mehran Chakraborty, Arup K. Wittrup, Karl Dane Eisen, Herman N. Hanson, Melissa Catherine Irvine, Darrell J Chakraborty, Arup K |
| author_sort | Wang, Shenshen |
| collection | MIT |
| description | Generation of potent antibodies by a mutation-selection process called affinity maturation is a key component of effective immune responses. Antibodies that protect against highly mutable pathogens must neutralize diverse strains. Developing effective immunization strategies to drive their evolution requires understanding how affinity maturation happens in an environment where variants of the same antigen are present. We present an in silico model of affinity maturation driven by antigen variants which reveals that induction of cross-reactive antibodies often occurs with low probability because conflicting selection forces, imposed by different antigen variants, can frustrate affinity maturation. We describe how variables such as temporal pattern of antigen administration influence the outcome of this frustrated evolutionary process. Our calculations predict, and experiments in mice with variant gp120 constructs of the HIV envelope protein confirm, that sequential immunization with antigen variants is preferred over a cocktail for induction of cross-reactive antibodies focused on the shared CD4 binding site epitope. |
| first_indexed | 2024-09-23T10:15:29Z |
| format | Article |
| id | mit-1721.1/101768 |
| institution | Massachusetts Institute of Technology |
| language | en_US |
| last_indexed | 2024-09-23T10:15:29Z |
| publishDate | 2016 |
| publisher | Elsevier |
| record_format | dspace |
| spelling | mit-1721.1/1017682022-09-26T16:50:30Z Manipulating the Selection Forces during Affinity Maturation to Generate Cross-Reactive HIV Antibodies Wang, Shenshen Mata-Fink, Jordi Kriegsman, Barry Irvine, Darrell J. Eisen, Herman N. Burton, Dennis R. Kardar, Mehran Chakraborty, Arup K. Wittrup, Karl Dane Eisen, Herman N. Hanson, Melissa Catherine Irvine, Darrell J Chakraborty, Arup K Massachusetts Institute of Technology. Institute for Medical Engineering & Science Massachusetts Institute of Technology. Department of Biological Engineering Massachusetts Institute of Technology. Department of Biology Massachusetts Institute of Technology. Department of Chemical Engineering Massachusetts Institute of Technology. Department of Physics Ragon Institute of MGH, MIT and Harvard Koch Institute for Integrative Cancer Research at MIT Wang, Shenshen Mata-Fink, Jordi Kriegsman, Barry Hanson, Melissa Irvine, Darrell J. Eisen, Herman N. Wittrup, Karl Dane Kardar, Mehran Chakraborty, Arup K. Generation of potent antibodies by a mutation-selection process called affinity maturation is a key component of effective immune responses. Antibodies that protect against highly mutable pathogens must neutralize diverse strains. Developing effective immunization strategies to drive their evolution requires understanding how affinity maturation happens in an environment where variants of the same antigen are present. We present an in silico model of affinity maturation driven by antigen variants which reveals that induction of cross-reactive antibodies often occurs with low probability because conflicting selection forces, imposed by different antigen variants, can frustrate affinity maturation. We describe how variables such as temporal pattern of antigen administration influence the outcome of this frustrated evolutionary process. Our calculations predict, and experiments in mice with variant gp120 constructs of the HIV envelope protein confirm, that sequential immunization with antigen variants is preferred over a cocktail for induction of cross-reactive antibodies focused on the shared CD4 binding site epitope. Ragon Institute of MGH, MIT and Harvard Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery (Grant UM1AI100663) 2016-03-24T14:57:45Z 2016-03-24T14:57:45Z 2015-02 2014-10 Article http://purl.org/eprint/type/JournalArticle 00928674 1097-4172 http://hdl.handle.net/1721.1/101768 Wang, Shenshen, Jordi Mata-Fink, Barry Kriegsman, Melissa Hanson, Darrell J. Irvine, Herman N. Eisen, Dennis R. Burton, K. Dane Wittrup, Mehran Kardar, and Arup K. Chakraborty. “Manipulating the Selection Forces During Affinity Maturation to Generate Cross-Reactive HIV Antibodies.” Cell 160, no. 4 (February 2015): 785–797. https://orcid.org/0000-0003-2398-5896 https://orcid.org/0000-0002-6064-0531 https://orcid.org/0000-0003-1268-9602 https://orcid.org/0000-0002-1112-5912 en_US http://dx.doi.org/10.1016/j.cell.2015.01.027 Cell Creative Commons Attribution-NonCommercial-NoDerivs License http://creativecommons.org/licenses/by-nc-nd/4.0/ application/pdf Elsevier PMC |
| spellingShingle | Wang, Shenshen Mata-Fink, Jordi Kriegsman, Barry Irvine, Darrell J. Eisen, Herman N. Burton, Dennis R. Kardar, Mehran Chakraborty, Arup K. Wittrup, Karl Dane Eisen, Herman N. Hanson, Melissa Catherine Irvine, Darrell J Chakraborty, Arup K Manipulating the Selection Forces during Affinity Maturation to Generate Cross-Reactive HIV Antibodies |
| title | Manipulating the Selection Forces during Affinity Maturation to Generate Cross-Reactive HIV Antibodies |
| title_full | Manipulating the Selection Forces during Affinity Maturation to Generate Cross-Reactive HIV Antibodies |
| title_fullStr | Manipulating the Selection Forces during Affinity Maturation to Generate Cross-Reactive HIV Antibodies |
| title_full_unstemmed | Manipulating the Selection Forces during Affinity Maturation to Generate Cross-Reactive HIV Antibodies |
| title_short | Manipulating the Selection Forces during Affinity Maturation to Generate Cross-Reactive HIV Antibodies |
| title_sort | manipulating the selection forces during affinity maturation to generate cross reactive hiv antibodies |
| url | http://hdl.handle.net/1721.1/101768 https://orcid.org/0000-0003-2398-5896 https://orcid.org/0000-0002-6064-0531 https://orcid.org/0000-0003-1268-9602 https://orcid.org/0000-0002-1112-5912 |
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