Using designed ankyrin repeat proteins (DARPins) technology, we discovered an α-helical conformation of the third variable (V3) loop on the human immunodeficiency virus 1 (HIV-1) envelope glycoprotein that renders the virus susceptible to broad neutralization at an intermediate entry stage after binding the CD4 receptor. Our results highlight the potential of post-attachment neutralization and enable exploitation of this helical region for inhibitor and vaccine design.
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References
Shaik, M. M. et al. Structural basis of coreceptor recognition by HIV-1 envelope spike. Nature 565, 318–323 (2019). An article describing the interaction of the V3 loop with the HIV-1 coreceptor CCR5 during entry.
Haynes, B. F. et al. Strategies for HIV-1 vaccines that induce broadly neutralizing antibodies. Nat. Rev. Immunol. 23, 142–158 (2023). A review article describing strategies for bnAb induction.
Plückthun, A. Designed ankyrin repeat proteins (DARPins): binding proteins for research, diagnostics, and therapy. Annu. Rev. Pharmacol. Toxicol. 55, 489–511 (2015). A review article describing the DARPins technology.
Friedrich, N. et al. Distinct conformations of the HIV-1 V3 loop crown are targetable for broad neutralization. Nat. Commun. 12, 6705 (2021). A publication describing broadly neutralizing V3-targeting DARPins.
Mann, A. et al. Conformation-dependent recognition of HIV gp120 by designed ankyrin repeat proteins provides access to novel HIV entry inhibitors. J. Virol. 87, 5868–5881 (2013). A publication describing V3-directed DARPins.
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This is a summary of: Glögl, M. et al. Trapping the HIV-1 V3 loop in a helical conformation enables broad neutralization. Nat. Struct. Mol. Biol. https://doi.org/10.1038/s41594-023-01062-z (2023).
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Conserved HIV-1 V3 loop helix offers potential for broad neutralization. Nat Struct Mol Biol 30, 1256–1257 (2023). https://doi.org/10.1038/s41594-023-01063-y
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DOI: https://doi.org/10.1038/s41594-023-01063-y
