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Cell Host Microbe. 2018 Jun 13;23(6):759-765.e6. doi: 10.1016/j.chom.2018.04.018. Epub 2018 May 31.

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

Author information

1
Duke Human Vaccine Institute, Duke University School of Medicine, Durham, NC 27710, USA; Department of Medicine, Duke University School of Medicine, Durham, NC 22710, USA. Electronic address: kevin.wiehe@duke.edu.
2
Duke Human Vaccine Institute, Duke University School of Medicine, Durham, NC 27710, USA; Department of Medicine, Duke University School of Medicine, Durham, NC 22710, USA.
3
Duke Human Vaccine Institute, Duke University School of Medicine, Durham, NC 27710, USA; Department of Immunology, Duke University School of Medicine, Durham, NC 22710, USA.
4
Duke Human Vaccine Institute, Duke University School of Medicine, Durham, NC 27710, USA.
5
Department of Microbiology, Boston University School of Medicine, Boston, MA 02215, USA; Department of Mathematics and Statistics, Boston Univeristy, Boston, MA 02215, USA.
6
Duke Human Vaccine Institute, Duke University School of Medicine, Durham, NC 27710, USA; Department of Surgery, Duke University School of Medicine, Durham, NC 27710, USA.
7
Duke Human Vaccine Institute, Duke University School of Medicine, Durham, NC 27710, USA; Department of Medicine, Duke University School of Medicine, Durham, NC 22710, USA; Department of Pathology, Duke University School of Medicine, Durham, NC 27710, USA.
8
Duke Human Vaccine Institute, Duke University School of Medicine, Durham, NC 27710, USA; Department of Medicine, Duke University School of Medicine, Durham, NC 22710, USA. Electronic address: barton.haynes@duke.edu.

Abstract

HIV-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.

PMID:
29861171
PMCID:
PMC6002614
DOI:
10.1016/j.chom.2018.04.018
[Indexed for MEDLINE]
Free PMC Article

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