Trapping the HIV-1 V3 loop in a helical conformation enables broad neutralization.

Autor: Glögl M; Institute for Medical Virology, University of Zurich (UZH), Zurich, Switzerland., Friedrich N; Institute for Medical Virology, University of Zurich (UZH), Zurich, Switzerland., Cerutti G; Zuckerman Mind Brain Behavior Institute, Columbia University, New York, NY, USA., Lemmin T; Institute for Medical Virology, University of Zurich (UZH), Zurich, Switzerland., Kwon YD; Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA., Gorman J; Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA., Maliqi L; Institute for Medical Virology, University of Zurich (UZH), Zurich, Switzerland., Mittl PRE; Department of Biochemistry, University of Zurich (UZH), Zurich, Switzerland., Hesselman MC; Institute for Medical Virology, University of Zurich (UZH), Zurich, Switzerland., Schmidt D; Institute for Medical Virology, University of Zurich (UZH), Zurich, Switzerland., Weber J; Institute for Medical Virology, University of Zurich (UZH), Zurich, Switzerland., Foulkes C; Institute for Medical Virology, University of Zurich (UZH), Zurich, Switzerland., Dingens AS; Fred Hutchinson Cancer Research Center, Seattle, WA, USA., Bylund T; Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA., Olia AS; Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA., Verardi R; Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA., Reinberg T; Department of Biochemistry, University of Zurich (UZH), Zurich, Switzerland., Baumann NS; Institute for Medical Virology, University of Zurich (UZH), Zurich, Switzerland., Rusert P; Institute for Medical Virology, University of Zurich (UZH), Zurich, Switzerland., Dreier B; Department of Biochemistry, University of Zurich (UZH), Zurich, Switzerland., Shapiro L; Zuckerman Mind Brain Behavior Institute, Columbia University, New York, NY, USA.; Department of Biochemistry and Molecular Biophysics, Columbia University, New York, NY, USA., Kwong PD; Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA., Plückthun A; Department of Biochemistry, University of Zurich (UZH), Zurich, Switzerland., Trkola A; Institute for Medical Virology, University of Zurich (UZH), Zurich, Switzerland. trkola.alexandra@virology.uzh.ch.
Jazyk: angličtina
Zdroj: Nature structural & molecular biology [Nat Struct Mol Biol] 2023 Sep; Vol. 30 (9), pp. 1323-1336. Date of Electronic Publication: 2023 Aug 21.
DOI: 10.1038/s41594-023-01062-z
Abstrakt: The third variable (V3) loop on the human immunodeficiency virus 1 (HIV-1) envelope glycoprotein trimer is indispensable for virus cell entry. Conformational masking of V3 within the trimer allows efficient neutralization via V3 only by rare, broadly neutralizing glycan-dependent antibodies targeting the closed prefusion trimer but not by abundant antibodies that access the V3 crown on open trimers after CD4 attachment. Here, we report on a distinct category of V3-specific inhibitors based on designed ankyrin repeat protein (DARPin) technology that reinstitute the CD4-bound state as a key neutralization target with up to >90% breadth. Broadly neutralizing DARPins (bnDs) bound V3 solely on open envelope and recognized a four-turn amphipathic α-helix in the carboxy-terminal half of V3 (amino acids 314-324), which we termed 'αV3C'. The bnD contact surface on αV3C was as conserved as the CD4 binding site. Molecular dynamics and escape mutation analyses underscored the functional relevance of αV3C, highlighting the potential of αV3C-based inhibitors and, more generally, of postattachment inhibition of HIV-1.
(© 2023. The Author(s).)
Databáze: MEDLINE
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