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Lipidomimetic compounds act as HIV-1 entry inhibitors by altering viral membrane structure.
Front. Immunol. 9, DOI: 10.3389/fimmu.2018.01983 (2018)
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 membrane order. The compounds' effects on membrane order were reproduced in liposomes generated from extracted HIV lipids and thus independent both of virion proteins and of membrane leaflet asymmetry. Remarkably, increase of membrane order by J391B required phosphatidylserine, a lipid enriched in the HIV envelope. Counterintuitively, mixtures of two compounds with opposite effects on membrane order, J582C and J391B, did not neutralize each other but synergistically inhibited HIV infection. Thus, altering membrane order, which can occur by different mechanisms, constitutes a novel antiviral mode of action that may be of general relevance for enveloped viruses and difficult to overcome by resistance development.
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Publication type
Article: Journal article
Document type
Scientific Article
Keywords
Lipidomimetics ; Hiv-1 Envelope ; Lipid Raft Modulation ; Laurdan ; Membrane Order ; Hiv Fusion Inhibitors ; Phosphatidylserine; Human-immunodeficiency-virus; Virion-associated Cholesterol; Vesicular Stomatitis-virus; Murine Leukemia-virus; Laurdan Fluorescence; Enveloped Viruses; Lipid Rafts; Plasma-membranes; T-lymphocytes; In-vitro
Language
Publication Year
2018
HGF-reported in Year
2018
ISSN (print) / ISBN
1664-3224
e-ISSN
1664-3224
Journal
Frontiers in Immunology
Quellenangaben
Volume: 9
Publisher
Frontiers
Publishing Place
Avenue Du Tribunal Federal 34, Lausanne, Ch-1015, Switzerland
Reviewing status
Peer reviewed
Institute(s)
Institute of Pancreatic Islet Research (IPI)
POF-Topic(s)
90000 - German Center for Diabetes Research
Research field(s)
Helmholtz Diabetes Center
PSP Element(s)
G-502600-002
WOS ID
WOS:000443619300001
Erfassungsdatum
2018-09-14