Journal
IMMUNITY
Volume 50, Issue 6, Pages 1513-+Publisher
CELL PRESS
DOI: 10.1016/j.immuni.2019.04.014
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Funding
- NIH [UM1 AI068618, P01 AI057005, P50 GM082545-06]
- Bill and Melinda Gates Foundation
- National Institute of Allergy and Infectious Diseases of the NIH [HIVRAD P01 AI100148, R01 AI131722]
- Bill and Melinda Gates Foundation Collaboration for AIDS Vaccine Discovery [OPP1124068, 1146996]
- NIH Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery (CHAVI-ID) [1UM1 AI100663-01]
- European Research Council [ERC-StG639961]
- German Center for Infection Research (DZIF)
- Vaccine Research Center, NIAID/NIH
- Ernst Jung Career Advancement Award for Medical Research
- National Center for Advancing Translational Sciences (NCATS, NIH Clinical and Translational Science Award [CTSA] program) [UL1 TR001866]
- DZIF [TI 07.002]
- Hanna Gray Fellowship Program from the Howard Hughes Medical Institute
- Postdoctoral Enrichment Program from the Burroughs Wellcome Fund
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Broadly neutralizing antibodies (bNAbs) against HIV-1 envelope (Env) inform vaccine design and are potential therapeutic agents. We identified SF12 and related bNAbs with up to 62% neutralization breadth from an HIV-infected donor. SF12 recognized a glycan-dominated epitope on Env's silent face and was potent against Glade AE viruses, which o are poorly covered by V3-glycan bNAbs. A 3.3 angstrom cryo-EM structure of a SF12-Env trimer complex showed additional contacts to Env protein residues by SF12 compared with VRC-PG05, the only other known donor-derived silent-face antibody, explaining SF12's increased neutralization breadth, potency, and resistance to Env mutation routes. Asymmetric binding of SF12 was associated with distinct N-glycan conformations across Env protomers, demonstrating intra-Env glycan heterogeneity. Administrating SF12 to HIV-1-infected humanized mice suppressed viremia and selected for viruses lacking the N448(gp)(120) glycan. Effective bNAbs can therefore be raised against HIV-1 Env's silent face, suggesting their potential for HIV-1 prevention, therapy, and vaccine development.
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