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 Medjournal_title
Science translational medicineauthors
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 CAdoi
10.1126/scitranslmed.aai7514subject
Has Abstractpub_date
2017-03-15 00:00:00issue
381eissn
1946-6234issn
1946-6242pii
9/381/eaai7514journal_volume
9pub_type
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