HIV Envelope Glycoform Heterogeneity and Localized Diversity Govern the Initiation and Maturation of a V2 Apex Broadly Neutralizing Antibody Lineage
Elise Landais
(1)
,
Ben Murrell
(2)
,
Bryan Briney
(3)
,
Sasha Murrell
(4)
,
Kimmo Rantalainen
(4)
,
Zachary T Berndsen
(4)
,
Alejandra Ramos
(5)
,
Lalinda Wickramasinghe
(5)
,
Melissa Laird Smith
(6)
,
Kemal Eren
(7)
,
Natalia de Val
(5)
,
Mengyu Wu
(4)
,
Audrey Cappelletti
(5)
,
Jeffrey Umotoy
(5)
,
Yolanda Lie
(8)
,
Terri Wrin
(8)
,
Paul Algate
(9)
,
Po-Ying Chan-Hui
(9)
,
Etienne Karita
(10)
,
Andrew B Ward
(11)
,
Ian A Wilson
(3)
,
Dennis R Burton
(5)
,
Davey Smith
,
Sergei L Kosakovsky Pond
(2)
,
Pascal Poignard
(12)
1
International AIDS Vaccine Initiative Neutralizing Antibody Center
2 MED - UC San Diego - Department of Medicine [Univ California San Diego]
3 Department of Immunology and Microbial Sciences
4 Department of Integrative Structural and Computational Biology [La Jolla, CA, USA]
5 International AIDS Vaccine Initiative Neutralizing Antibody Center
6 MSSM - Icahn School of Medicine at Mount Sinai [New York]
7 Biomedical Informatics
8 Monogram Biosciences
9 Theraclone Sciences, Inc.
10 Rwanda-Zambia HIV Research Group
11 Department of Integrative Structural and Computational Biology [Scripps Research Institute]
12 IBS - UMR 5075 - Institut de biologie structurale
2 MED - UC San Diego - Department of Medicine [Univ California San Diego]
3 Department of Immunology and Microbial Sciences
4 Department of Integrative Structural and Computational Biology [La Jolla, CA, USA]
5 International AIDS Vaccine Initiative Neutralizing Antibody Center
6 MSSM - Icahn School of Medicine at Mount Sinai [New York]
7 Biomedical Informatics
8 Monogram Biosciences
9 Theraclone Sciences, Inc.
10 Rwanda-Zambia HIV Research Group
11 Department of Integrative Structural and Computational Biology [Scripps Research Institute]
12 IBS - UMR 5075 - Institut de biologie structurale
Résumé
Understanding how broadly neutralizing antibodies (bnAbs) to HIV envelope (Env) develop during natural infection can help guide the rational design of an HIV vaccine. Here, we described a bnAb lineage targeting the Env V2 apex and the Ab-Env co-evolution that led to development of neutralization breadth. The lineage Abs bore an anionic heavy chain complementarity-determining region 3 (CDRH3) of 25 amino acids, among the shortest known for this class of Abs, and achieved breadth with only 10% nucleotide somatic hypermutation and no insertions or deletions. The data suggested a role for Env glycoform heterogeneity in the activation of the lineage germline B cell. Finally, we showed that localized diversity at key V2 epitope residues drove bnAb maturation toward breadth, mirroring the Env evolution pattern described for another donor who developed V2-apex targeting bnAbs. Overall, these findings suggest potential strategies for vaccine approaches based on germline-targeting and serial immunogen design.