Manipulating the Selection Forces during Affinity Maturation to Generate Cross-Reactive HIV Antibodies

• Main Authors: Wang, Shenshen (Contributor), Mata-Fink, Jordi (Contributor), Kriegsman, Barry (Contributor), Irvine, Darrell J (Author), Eisen, Herman N (Author), Burton, Dennis R (Author), Kardar, Mehran (Contributor), Chakraborty, Arup K (Author), Wittrup, Karl Dane (Contributor), Eisen, Herman N. (Contributor), Hanson, Melissa Catherine (Author), Irvine, Darrell J (Author), Chakraborty, Arup K (Author)
• Other Authors: Massachusetts Institute of Technology. Institute for Medical Engineering & Science (Contributor), Massachusetts Institute of Technology. Department of Biological Engineering (Contributor), Massachusetts Institute of Technology. Department of Biology (Contributor), Massachusetts Institute of Technology. Department of Chemical Engineering (Contributor), Massachusetts Institute of Technology. Department of Physics (Contributor), Ragon Institute of MGH, MIT and Harvard (Contributor), Koch Institute for Integrative Cancer Research at MIT (Contributor), Hanson, Melissa (Contributor), Irvine, Darrell J. (Contributor), Chakraborty, Arup K. (Contributor)
• Format: Article
• Language: English
• Published: Elsevier, 2016-03-24T14:57:45Z.
• Subjects: Article
• Online Access: Get fulltext

 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.