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

Nature Structural & Molecular Biology
Maro IliopoulouSergi Padilla-Parra

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.

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Citations

Nov 26, 2019·Physical Chemistry Chemical Physics : PCCP·Lin-Tai Da, Mengna Lin
Feb 16, 2020·Viruses·Irene Carlon-Andres, Sergi Padilla-Parra
Jun 6, 2020·The EMBO Journal·Daniel RozbeskyEdith Yvonne Jones
Apr 5, 2020·Viruses·Pablo CarravillaChristian Eggeling
May 16, 2020·Frontiers in Bioengineering and Biotechnology·Mai IzumidaYoshinao Kubo
Jul 3, 2019·Trends in Microbiology·Bing Chen
Apr 27, 2021·Critical Reviews in Microbiology·Sriram YandrapallySharmistha Banerjee
May 1, 2021·Viruses·Tianshu XiaoBing Chen
Jun 3, 2021·Viruses·Ashley Lauren Bennett, Rory Henderson
May 18, 2021·Frontiers in Microbiology·Romina Cabrera-RodríguezAgustín Valenzuela-Fernández
Dec 18, 2019·Journal of Chemical Information and Modeling·Mengna Lin, Lin-Tai Da

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Methods Mentioned

BETA
fluorescence microscopy
fluorescence fluctuation spectroscopy
light microscopy
super-resolution localization microscopy
transfection
fluorescence imaging
fluorescence
fluorescence resonance

Software Mentioned

Coot
dSTORM
Pymol
R
Fiji ImageJ
GitHub
SymPhoTime
BitPlane
ImageJ
Imaris

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