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

Journal Article (Journal Article)

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.

Full Text

Duke Authors

Cited Authors

  • Bonsignori, M; Kreider, EF; Fera, D; Meyerhoff, RR; Bradley, T; Wiehe, K; Alam, SM; Aussedat, B; Walkowicz, WE; Hwang, K-K; Saunders, KO; Zhang, R; Gladden, MA; Monroe, A; Kumar, A; Xia, S-M; Cooper, M; Louder, MK; McKee, K; Bailer, RT; Pier, BW; Jette, CA; Kelsoe, G; Williams, WB; Morris, L; Kappes, J; Wagh, K; Kamanga, G; Cohen, MS; Hraber, PT; Montefiori, DC; Trama, A; Liao, H-X; Kepler, TB; Moody, MA; Gao, F; Danishefsky, SJ; Mascola, JR; Shaw, GM; Hahn, BH; Harrison, SC; Korber, BT; Haynes, BF

Published Date

  • March 2017

Published In

Volume / Issue

  • 9 / 381

Start / End Page

  • eaai7514 -

PubMed ID

  • 28298420

Pubmed Central ID

  • PMC5562350

Electronic International Standard Serial Number (EISSN)

  • 1946-6242

International Standard Serial Number (ISSN)

  • 1946-6234

Digital Object Identifier (DOI)

  • 10.1126/scitranslmed.aai7514


  • eng