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Nat Commun. 2018 Oct 8;9(1):4136. doi: 10.1038/s41467-018-06424-6.

Sequencing HIV-neutralizing antibody exons and introns reveals detailed aspects of lineage maturation.

Author information

1
Department of Chemical Engineering, The University of Texas at Austin, Austin, TX, 78712, USA.
2
Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, 20892, USA.
3
Center for HIV and STIs, National Institute for Communicable Diseases of the National Health Laboratory Service (NHLS), Johannesburg, 2131, South Africa.
4
Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, 2050, South Africa.
5
Department of Molecular Biosciences, The University of Texas at Austin, Austin, TX, 78712, USA.
6
The University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA.
7
Geisel School of Medicine, Dartmouth College, Hanover, NH, 03755, USA.
8
Centre for the AIDS Programme of Research in South Africa (CAPRISA), University of KwaZulu-Natal, Congella, 4013, South Africa.
9
Department of Epidemiology, Columbia University, New York, NY, 10032, USA.
10
Department of Chemical Engineering, The University of Texas at Austin, Austin, TX, 78712, USA. gg@che.utexas.edu.
11
Department of Molecular Biosciences, The University of Texas at Austin, Austin, TX, 78712, USA. gg@che.utexas.edu.
12
Department of Biomedical Engineering, The University of Texas at Austin, Austin, TX, 78712, USA. gg@che.utexas.edu.

Abstract

The developmental pathways of broadly neutralizing antibodies (bNAbs) against HIV are of great importance for the design of immunogens that can elicit protective responses. Here we show the maturation features of the HIV-neutralizing anti-V1V2 VRC26 lineage by simultaneously sequencing the exon together with the downstream intron of VRC26 members. Using the mutational landscapes of both segments and the selection-free nature of the intron region, we identify multiple events of amino acid mutational convergence in the complementarity-determining region 3 (CDR3) of VRC26 members, and determine potential intermediates with diverse CDR3s to a late stage bNAb from 2 years prior to its isolation. Moreover, we functionally characterize the earliest neutralizing intermediates with critical CDR3 mutations, with some emerging only 14 weeks after initial lineage detection and containing only ~6% V gene mutations. Our results thus underscore the utility of analyzing exons and introns simultaneously for studying antibody maturation and repertoire selection.

PMID:
30297708
PMCID:
PMC6175870
DOI:
10.1038/s41467-018-06424-6
[Indexed for MEDLINE]
Free PMC Article

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