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

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.

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Citation

Published Version (Please cite this version)

10.1016/j.chom.2018.04.018

Publication Info

Wiehe, Kevin, Todd Bradley, R Ryan Meyerhoff, Connor Hart, Wilton B Williams, David Easterhoff, William J Faison, Thomas B Kepler, et al. (2018). Functional Relevance of Improbable Antibody Mutations for HIV Broadly Neutralizing Antibody Development. Cell host & microbe, 23(6). pp. 759–765.e6. 10.1016/j.chom.2018.04.018 Retrieved from https://hdl.handle.net/10161/17301.

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Scholars@Duke

Wiehe

Kevin J Wiehe

Norman L. Letvin Associate Professor in Medicine

Dr. Kevin Wiehe is the associate director of research, director of computational biology and co-director of the Quantitative Research Division at the Duke Human Vaccine Institute (DHVI). He has over 20 years of experience in the field of computational biology and has expertise in computational structural biology, computational genomics, and computational immunology.

For the past decade, he has applied his unique background to developing computational approaches for studying the B cell response in both the infection and vaccination settings. He has utilized his expertise in computational structural biology to structurally model and characterize HIV and influenza antibody recognition. Dr. Wiehe has utilized his expertise in computational genomics and computational immunology to develop software to analyze large scale next generation sequencing data of antibody repertoires as well as develop computational programs for estimating antibody mutation probabilities. Dr. Wiehe has shown that low probability antibody mutations can act as rate-limiting steps in the development of broadly neutralizing antibodies in HIV.

Through his PhD, postdoc work, and now his roles at DHVI, Dr. Wiehe always approaches the analysis and the scientific discovery process from a structural biology perspective. Supporting the Duke Center for HIV Structural Biology (DCHSB), Dr. Wiehe will conduct antibody sequence analysis for antibodies used in computational and molecular modeling analyses conducted.

Bradley

Todd Christopher Bradley

Assistant Professor in Medicine
Meyerhoff

Ryan Meyerhoff

House Staff

Program Start Year:  2013
Barton Haynes Laboratory

"Studies of Immunogens to Induce Broadly Neutralizing HIV Antibodies"


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