Functional Relevance of Improbable Antibody Mutations for HIV Broadly Neutralizing Antibody Development

Kevin Wiehe,Todd Bradley,R Ryan Meyerhoff,Connor Hart,Wilton B Williams,David Easterhoff,William J Faison,Thomas B Kepler,Kevin O Saunders,S Munir Alam,Mattia Bonsignori,Barton F Haynes

doi:10.1016/j.chom.2018.04.018

Abstract

SummaryHIV-1 broadly neutralizing antibodies (bnAbs) require high levels of activation-induced cytidine deaminase (AID)-catalyzed somatic mutations for optimal neutralization potency. Probable mutations occur at sites of frequent AID activity, while improbable mutations occur where AID activity is infrequent. One bottleneck for induction of bnAbs is the evolution of viral envelopes (Envs) that can select bnAb B cell receptors (BCR) with improbable mutations. Here we define the probability of bnAb mutations and demonstrate the functional significance of key improbable mutations in three bnAb B cell lineages. We show that bnAbs are enriched for improbable mutations, which implies that their elicitation will be critical for successful vaccine induction of potent bnAb B cell lineages. We discuss a mutation-guided vaccine strategy for identification of Envs that can select B cells with BCRs that have key improbable mutations required for bnAb development.

Highlights

T bnAbs (Georgiev et al, 2014; Jardine et al, 2016b)
Shorter maturation pathways to neutralization breadth involving a critical subset of mutations are desirable, because antibody mutation levels induced by vaccines seldom reach the mutation frequencies observed in bnAbs (Easterhoff et al, 2017; Moody et al, 2011). Within this subset of critical mutations, some mutations may be probable and easy to elicit, whereas other mutations may be improbable and very challenging to elicit due to biases in how mutations arise during affinity maturation
We identified improbable mutations in the heavy chain of an early intermediate member of the lineage, reverted each to their respective germline-encoded amino acids, and tested antibody mutants for neutralization against heterologous, difficult-to-neutralize (Seaman et al, 2010), CH235-sensitive viruses (Figures 1A and S1A)

Summary

Graphical Abstract

Not all mutations during B cell affinity maturation are probable. Wiehe et al show that HIV-1 broadly neutralizing antibodies (bnAbs) are enriched with lowprobability mutations and that these improbable mutations are often critical for HIV-1 bnAb neutralization breadth, making improbable mutations key targets for selection with vaccines. 2018, Cell Host & Microbe 23, 759–765 June 13, 2018 a 2018 The Authors.

SUMMARY

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