title: Manipulating the selection forces during affinity maturation to generate cross-reactive HIV antibodies.
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.
authors: Ragon 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.
authors: Shenshen
authors: S
authors: Wang
authors: Ragon Institute of MGH, MIT, and Harvard, Cambridge, MA 02139; Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139.
authors: Jordi
authors: J
authors: Mata-Fink
authors: Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139.
authors: Barry
authors: B
authors: Kriegsman
authors: Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139.
authors: Melissa
authors: M
authors: Hanson
authors: Ragon 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.
authors: Darrell J
authors: DJ
authors: Irvine
authors: Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139; Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139.
authors: Herman N
authors: HN
authors: Eisen
authors: Ragon Institute of MGH, MIT, and Harvard, Cambridge, MA 02139; Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, CA 92037.
authors: Dennis R
authors: DR
authors: Burton
authors: Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139; Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139.
authors: K Dane
authors: KD
authors: Wittrup
authors: Department of Physics, Massachusetts Institute of Technology, Cambridge, MA 02139.
authors: Mehran
authors: M
authors: Kardar
authors: Ragon 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.
authors: Arup K
authors: AK
authors: Chakraborty
mesh_terms: D000818:Animals; D057134:Antibodies, Neutralizing / Q000276:immunology*; D000914:Antibodies, Viral / Q000276:immunology*; D000940:Antigenic Variation; D001402:B-Lymphocytes / Q000276:immunology; D003198:Computer Simulation; D003429:Cross Reactions; D015699:HIV Envelope Protein gp120 / Q000235:genetics / Q000276:immunology*; D015497:HIV-1 / Q000276:immunology; D051379:Mice
chemical_list: D057134:Antibodies, Neutralizing; D000914:Antibodies, Viral; D015699:HIV Envelope Protein gp120; C514793:gp120 protein, Human immunodeficiency virus 1