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

Erik L. Johnson, Nicole A. Doria-Rose, Jason Gorman, Jinal N. Bhiman, Chaim A. Schramm, Ashley Q. Vu, William H. Law, Baoshan Zhang, Valerie Bekker, Salim S. Abdool Karim, Gregory C. Ippolito, Lynn Morris, Penny L. Moore, Peter D. Kwong, John R. Mascola and George Georgiou ()
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Erik L. Johnson: The University of Texas at Austin
Nicole A. Doria-Rose: National Institutes of Health
Jason Gorman: National Institutes of Health
Jinal N. Bhiman: National Institute for Communicable Diseases of the National Health Laboratory Service (NHLS)
Chaim A. Schramm: National Institutes of Health
Ashley Q. Vu: The University of Texas at Austin
William H. Law: National Institutes of Health
Baoshan Zhang: National Institutes of Health
Valerie Bekker: National Institute for Communicable Diseases of the National Health Laboratory Service (NHLS)
Salim S. Abdool Karim: University of KwaZulu-Natal
Gregory C. Ippolito: The University of Texas at Austin
Lynn Morris: National Institute for Communicable Diseases of the National Health Laboratory Service (NHLS)
Penny L. Moore: National Institute for Communicable Diseases of the National Health Laboratory Service (NHLS)
Peter D. Kwong: National Institutes of Health
John R. Mascola: National Institutes of Health
George Georgiou: The University of Texas at Austin

Nature Communications, 2018, vol. 9, issue 1, 1-13

Abstract: 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.

Date: 2018
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DOI: 10.1038/s41467-018-06424-6

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