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

TitleManipulating the Selection Forces during Affinity Maturation to Generate Cross-Reactive HIV Antibodies.
Publication TypeJournal Article
Year of Publication2015
AuthorsWang S, Mata-Fink J, Kriegsman B, Hanson M, Irvine DJ, Eisen HN, Burton DR, K Wittrup D, Kardar M, Chakraborty AK
JournalCell
Volume160
Issue4
Pagination785-97
Date Published02/12/2015
ISSN1097-4172
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.

DOI10.1016/j.cell.2015.01.027
Alternate JournalCell
PubMed ID25662010
Grant ListR01 AI033292 / AI / NIAID NIH HHS / United States
UM1 AI100663 / AI / NIAID NIH HHS / United States
CHAVI-ID: 
1
Cover Picture: