Staged induction of HIV-1 glycan-dependent broadly neutralizing antibodies.

Abstract:

:A preventive HIV-1 vaccine should induce HIV-1-specific broadly neutralizing antibodies (bnAbs). However, bnAbs generally require high levels of somatic hypermutation (SHM) to acquire breadth, and current vaccine strategies have not been successful in inducing bnAbs. Because bnAbs directed against a glycosylated site adjacent to the third variable loop (V3) of the HIV-1 envelope protein require limited SHM, the V3-glycan epitope is an attractive vaccine target. By studying the cooperation among multiple V3-glycan B cell lineages and their coevolution with autologous virus throughout 5 years of infection, we identify key events in the ontogeny of a V3-glycan bnAb. Two autologous neutralizing antibody lineages selected for virus escape mutations and consequently allowed initiation and affinity maturation of a V3-glycan bnAb lineage. The nucleotide substitution required to initiate the bnAb lineage occurred at a low-probability site for activation-induced cytidine deaminase activity. Cooperation of B cell lineages and an improbable mutation critical for bnAb activity defined the necessary events leading to breadth in this V3-glycan bnAb lineage. These findings may, in part, explain why initiation of V3-glycan bnAbs is rare, and suggest an immunization strategy for inducing similar V3-glycan bnAbs.

journal_name

Sci Transl Med

authors

Bonsignori M,Kreider EF,Fera D,Meyerhoff RR,Bradley T,Wiehe K,Alam SM,Aussedat B,Walkowicz WE,Hwang KK,Saunders KO,Zhang R,Gladden MA,Monroe A,Kumar A,Xia SM,Cooper M,Louder MK,McKee K,Bailer RT,Pier BW,Jette CA

doi

10.1126/scitranslmed.aai7514

subject

Has Abstract

pub_date

2017-03-15 00:00:00

issue

381

eissn

1946-6234

issn

1946-6242

pii

9/381/eaai7514

journal_volume

9

pub_type

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