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

Posted by on in 2015
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  • Wang S1Mata-Fink J2Kriegsman B3Hanson M4Irvine DJ5Eisen HN6Burton DR7Wittrup KD8Kardar M9Chakraborty AK10. 2015. Cell. 160(4):785-97. doi: 10.1016/j.cell.2015.01.027. Epub 2015 Feb 5.
  • 1Ragon Institute of MGH, MIT, and Harvard, Cambridge, MA 02139; Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139; Department of Physics, Massachusetts Institute of Technology, Cambridge, MA 02139.
  • 2Ragon Institute of MGH, MIT, and Harvard, Cambridge, MA 02139; Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139.
  • 3Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139.
  • 4Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139.
  • 5Ragon Institute of MGH, MIT, and Harvard, Cambridge, MA 02139; Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139; Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139.
  • 6Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139; Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139.
  • 7Ragon Institute of MGH, MIT, and Harvard, Cambridge, MA 02139; Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, CA 92037.
  • 8Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139; Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139.
  • 9Department of Physics, Massachusetts Institute of Technology, Cambridge, MA 02139.
  • 10Ragon Institute of MGH, MIT, and Harvard, Cambridge, MA 02139; Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139; Department of Physics, Massachusetts Institute of Technology, Cambridge, MA 02139; Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139; Department of Chemistry, Massachusetts Institute of Technology, Cambridge, MA 02139; Institute for Medical Engineering and Science, Massachusetts Institute of Technology, Cambridge, MA 02139. Electronic address: arupc@mit.edu.

Abstract

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.

Copyright © 2015 Elsevier Inc. All rights reserved.

*The Chicken anti-CMYC used in this publication is a product of Gallus Immunotech Inc.

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