A dynamic three-step mechanism drives the HIV-1 pre-fusion reaction

Maro Iliopoulou, Rory Nolan, Luis Alvarez, Yasunori Watanabe, Charles A. Coomer, G. Maria Jakobsdottir, Thomas A. Bowden, Sergi Padilla-parra

Research output: Contribution to journalArticlepeer-review

28 Citations (Scopus)

Abstract

Little is known about the intermolecular dynamics and stoichiometry of the interactions of the human immunodeficiency virus type 1 (HIV-1) envelope (Env) protein with its receptors and co-receptors on the host cell surface. Here we analyze time-resolved HIV-1 Env interactions with T-cell surface glycoprotein CD4 (CD4) and C-C chemokine receptor type 5 (CCR5) or C-X-C chemokine receptor type 4 (CXCR4) on the surface of cells, by combining multicolor super-resolution localization microscopy (direct stochastic optical reconstruction microscopy) with fluorescence fluctuation spectroscopy imaging. Utilizing the primary isolate JR-FL and laboratory HXB2 strains, we reveal the time-resolved stoichiometry of CD4 and CCR5 or CXCR4 in the pre-fusion complex with HIV-1 Env. The HIV-1 Env pre-fusion dynamics for both R5- and X4-tropic strains consists of a three-step mechanism, which seems to differ in stoichiometry. Analyses with the monoclonal HIV-1-neutralizing antibody b12 indicate that the mechanism of inhibition differs between JR-FL and HXB2 Env. The molecular insights obtained here identify assemblies of HIV-1 Env with receptors and co-receptors as potential novel targets for inhibitor design.
Original languageEnglish
Pages (from-to)814-822
JournalNATURE STRUCTURAL AND MOLECULAR BIOLOGY
Volume25
Issue number9
Early online date27 Aug 2018
DOIs
Publication statusPublished - 1 Sept 2018

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