Lipidomimetic Compounds Act as HIV-1 Entry Inhibitors by Altering Viral Membrane Structure

Frontiers in Immunology
Jon A Nieto-GaraiH G Kräusslich

Abstract

The envelope of Human Immunodeficiency Virus type 1 (HIV-1) consists of a liquid-ordered membrane enriched in raft lipids and containing the viral glycoproteins. Previous studies demonstrated that changes in viral membrane lipid composition affecting membrane structure or curvature can impair infectivity. Here, we describe novel antiviral compounds that were identified by screening compound libraries based on raft lipid-like scaffolds. Three distinct molecular structures were chosen for mode-of-action studies, a sterol derivative (J391B), a sphingosine derivative (J582C) and a long aliphatic chain derivative (IBS70). All three target the viral membrane and inhibit virus infectivity at the stage of fusion without perturbing virus stability or affecting virion-associated envelope glycoproteins. Their effect did not depend on the expressed envelope glycoproteins or a specific entry route, being equally strong in HIV pseudotypes carrying VSV-G or MLV-Env glycoproteins. Labeling with laurdan, a reporter of membrane order, revealed different membrane structure alterations upon compound treatment of HIV-1, which correlated with loss of infectivity. J582C and IBS70 decreased membrane order in distinctive ways, whereas J391B increased m...Continue Reading

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Citations

Oct 1, 2019·Annual Review of Virology·Ellen Ketter, Glenn Randall
Jan 31, 2021·The Journal of Biological Chemistry·Eric BarklisFikadu G Tafesse
Feb 9, 2021·Advanced Science·Jon Ander Nieto-GaraiMaier Lorizate
Feb 23, 2021·Frontiers in Cell and Developmental Biology·Maurizio SoriceVincenzo Mattei

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Methods Mentioned

BETA
enzyme-linked immunosorbent assay
density gradient purification
FCS
PCR
fluorescence microscopy
transfection
electrophoresis
fluorescence spectroscopy
ELISA
density gradient centrifugation

Software Mentioned

SigmaPlot
CS Chem3D Ultra

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