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

• Published in: Cell 2015-02, Vol.160 (4), p.785-797
• Main Authors: Wang, Shenshen, Mata-Fink, Jordi, Kriegsman, Barry, Hanson, Melissa, Irvine, Darrell J., Eisen, Herman N., Burton, Dennis R., Wittrup, K. Dane, Kardar, Mehran, Chakraborty, Arup K.
• Format: Article
• Language: English
• Subjects: Animals; Antibodies, Neutralizing - immunology; Antibodies, Viral - immunology; Antigenic Variation; B-Lymphocytes - immunology; Computer Simulation; Cross Reactions; HIV Envelope Protein gp120 - genetics; HIV Envelope Protein gp120 - immunology; HIV-1 - immunology; Mice
• ISSN: 0092-8674; 1097-4172
• DOI: 10.1016/j.cell.2015.01.027

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. [Display omitted] •In silico model of affinity maturation driven by variant antigens•Conflicting selection forces due to antigen variants can frustrate maturation•Key variables that control evolution of cross-reactive antibodies identified•Sequential immunization favored for inducing cross-reactive antibodies In silico model of antibody affinity maturation explains why antibodies capable of cross-reacting with different variants of viral antigens are uncommon and shows that sequential immunization is effective at inducing cross-reactive HIV antibodies focused on the shared CD4 binding site.