Abstract
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 VH1-46-encoded CD4 binding site (CD4bs) bNAb with outstanding breadth (97%) and potency (GeoMean IC50 = 0.048 μg/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-Å cryo-EM structure of a 1-18-BG505SOSIP.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. Broadly neutralizing antibodies targeting the HIV-1 envelope protein are a promising option for prevention and treatment of HIV-1 infection. However, development of viral resistance can limit clinical efficacy. Schommers et al. identify a highly broad and potent antibody that targets the CD4 binding site of HIV-1. Compared with other potent CD4 binding site antibodies, it restricts the development of viral escape and effectively suppresses HIV-1 in vivo.
Original language | English |
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Pages (from-to) | 471-489.e22 |
Journal | Cell |
Volume | 180 |
Issue number | 3 |
DOIs | |
Publication status | Published - 6 Feb 2020 |
Keywords
- CD4 binding site
- HIV-1
- HIV-1 escape restriction
- broadly neutralizing antibodies
- cryogenic electron microscopy
- deep mutational scanning
- escape mutations
- humanized mice
- immunotherapy
- mutational antigenic profiling