Journal
CELL
Volume 180, Issue 3, Pages 471-+Publisher
CELL PRESS
DOI: 10.1016/j.cell.2020.01.010
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Funding
- German Center for Infection Research (DZIF)
- Graduate Research Fellowship Program (GRFP) of the National Science Foundation (NSF)
- Hans-Bockler Foundation
- Koln Fortune Program of the Faculty of Medicine of the University of Cologne
- Ernst Jung Career Advancement Award for Medical Research
- Federal Joint Committee (G-BA) [01VSF18036]
- Bill and Melinda Gates Foundation Collaboration for AIDS Vaccine Discovery (CAVD) grant [OPP1146996]
- National Institute of Allergy and Infectious Diseases (NIAID) of the National Institutes of Health (NIH) [R01 AI140891, HIVRAD P01 AI110657, HIVRAD P01 AI100148]
- NIH [P50 GM082545-06]
- German Research Foundation [CRC 1310, CRC 1279]
- DFG Heisenberg Program [KL2389/2-1]
- European Research Council [ERC-StG639961]
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Broadly neutralizing antibodies (bNAbs) represent a promising approach to prevent and treat HIV-1 infection. However, viral escape through mutation of the HIV-1 envelope glycoprotein (Env) limits clinical applications. Here we describe 1-18, a new V(H)1-46-encoded CD4 binding site (CD4bs) bNAb with outstanding breadth (97%) and potency (GeoMean IC50 = 0.048 mu g/mL). Notably, 1-18 is not susceptible to typical CD4bs escape mutations and effectively overcomes HIV-1 resistance to other CD4bs bNAbs. Moreover, mutational antigenic profiling uncovered restricted pathways of HIV-1 escape. Of most promise for therapeutic use, even 1-18 alone fully suppressed viremia in HIV-1-infected humanized mice without selecting for resistant viral variants. A 2.5-angstrom cryo-EM structure of a 1-18-BG505(SOSIP.664) Env complex revealed that these characteristics are likely facilitated by a heavy-chain insertion and increased inter-protomer contacts. The ability of 1-18 to effectively restrict HIV-1 escape pathways provides a new option to successfully prevent and treat HIV-1 infection.
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