Interaction of human immunodeficiency virus (HIV-1) fusion peptides with artificial lipid membranes

Slepushkin, Vladimir; Melikyan, Gregory B.; Sidorova, M.S.; Chumakov, V. M.; Andreev, S. M.; Manulyan, R.A.; Карамов, Э. В.

doi:10.1016/0006-291x(90)90768-i

Cited by 42 publications

(33 citation statements)

References 13 publications

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“…The free peptide causes fusion of liposomes and erythrocytes, and numerous mutational studies have shown strong correlations between fusion peptide-induced liposome fusion and viral/host cell fusion (5,(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25).…”

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Synthesis, Enhanced Fusogenicity, and Solid State NMR Measurements of Cross-Linked HIV-1 Fusion Peptides

Yang

Weliky

2003

Biochemistry

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In the HIV-1 gp41 and other viral fusion proteins, the minimal oligomerization state is believed to be trimeric with three N-terminal fusion peptides inserting into the membrane in close proximity. Previous studies have demonstrated that the fusion peptide by itself serves as a useful model fusion system, at least to the hemifusion stage in which the viral and target cell lipids are mixed. In the present study, HIV-1 fusion peptides were chemically synthesized and cross-linked at their C-termini to form dimers or trimers. C-terminal trimerization is their likely topology in the fusogenic form of the intact gp41 protein. The fusogenicity of the peptides was then measured in an intervesicle lipid mixing assay, and the assay results were compared to those of the monomer. For monomer, dimer, and trimer at peptide strand/lipid mol ratios between 0.0050 and 0.010, the final extent of lipid mixing for the dimer and trimer was 2-3 times greater than for the monomer. These data suggest that the higher local concentration of peptide strands in the cross-linked peptides enhances fusogenicity and that oligomerization of the fusion peptide in gp41 may enhance the rate of viral/target cell membrane fusion. For gp41, this effect is in addition to the role of the trimeric coiled-coil structure in bringing about apposition of viral and target cell membranes. NMR measurements on the membrane-associated dimeric fusion peptide were consistent with an extended structure at Phe-8, which is the same as has been observed for the membrane-bound monomer in the same lipid composition.Membrane fusion plays an essential role in enveloped virus entry into target host cells (1-4). Fusion is mediated by viral envelope proteins that contain apolar fusion peptide domains. The interaction between fusion peptides and lipids is believed to be one key event in initiating membrane fusion (5). Recent studies suggest that fusion protein regions other than the fusion peptide also interact with membranes and play a role in fusion (6-10).For HIV-1 1 and other enveloped viruses, the free ∼20-residue fusion peptide has been shown to be a useful model fusion system, at least to the hemifusion stage in which there is significant mixing between the viral and the target cell lipids. The free peptide causes fusion of liposomes and erythrocytes, and numerous mutational studies have shown strong correlations between fusion peptide-induced liposome fusion and viral/host cell fusion (5,(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25).For both the influenza hemagglutinin and the HIV-1 gp41 envelope proteins, there are crystal and NMR structures of soluble ectodomains in their fusogenic/final fusion conformations (26-32). These trimeric coiled-coil structures represent ∼140-residue sequences that begin near the C-terminus of the fusion peptide and end near the N-terminus of the viral transmembrane domain. For the influenza viral fusion protein, a pre-fusion structure has also been observed and is different from the fusogenic/post-fusion coiled-co...

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Synthesis, Enhanced Fusogenicity, and Solid State NMR Measurements of Cross-Linked HIV-1 Fusion Peptides

Yang

Weliky

2003

Biochemistry

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“…This domain, designated "fusion peptide", is considered to be directly involved in promoting fusion with the target membrane (12,13). Evidence supporting this hypothesis includes: (1) site-directed mutagenesis in the fusion peptide regions of several enveloped viruses including influenza virus (1,14), HIV 1 (15,16), simian immunodeficiency virus (17), and SV5 (18), which severely affect the fusogenic activity of the corresponding viruses; and (2) studies with synthetic peptides that mimic the fusion peptide region of several viruses including influenza virus (19,20), HIV (21)(22)(23), simian immunodeficiency virus (24), and Sendai virus (25). In addition, the photoactive lipid probe preferentially labeled the fusion peptide domain of influenza hemagglutinin (26).…”

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A Peptide Derived from a Conserved Domain of Sendai Virus Fusion Protein Inhibits Virus-Cell Fusion

Ghosh

Shai

1998

Journal of Biological Chemistry

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“…The binding of the gp120 subunit to target cell receptors (3-7) induces a conformational change in the glycoprotein, which results in the exposure of a previously hidden hydrophobic N-terminal stretch of gp41, designated the "fusion peptide" (8,9). Evidence supporting the role of the FP domain in mediating membrane fusion came from studies with intact envelope proteins (10 -12), as well as synthetic peptides used in model and biological systems (13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25). However, the molecular mechanism of membrane fusion is still poorly understood despite extensive studies done in both biological and model systems.…”

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Inhibition of HIV-1 Envelope Glycoprotein-mediated Cell Fusion by a DL-Amino Acid-containing Fusion Peptide

Gerber

Pritsker

Günther-Ausborn

et al. 2004

Journal of Biological Chemistry

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The N-terminal fusion peptide (FP) of human immunodeficiency virus-1 (HIV-1) is a potent inhibitor of cellcell fusion, possibly because of its ability to recognize the corresponding segments inside the fusion complex within the membrane. Here we show that a fusion peptide in which the highly conserved Ile 4 , Phe 8 , Phe 11 , and Ala 14 were replaced by their D-enantiomers (IFFA) is a potent inhibitor of cell-cell fusion. Fourier transform infrared spectroscopy confirmed that despite these drastic modifications, the peptide preserved most of its structure within the membrane. Fluorescence energy transfer studies demonstrated that the diastereomeric peptide interacted with the wild type FP, suggesting this segment as the target site for inhibition of membrane fusion. This is further supported by the similar localization of the wild type and IFFA FPs to microdomains in T cells and the preferred partitioning into ordered regions within sphingomyelin/phosphatidyl-choline/cholesterol giant vesicles. These studies provide insight into the mechanism of molecular recognition within the membrane milieu and may serve in designing novel HIV entry inhibitors.Specific fusion proteins, located on the surface of viral membranes, mediate membrane fusion (1). The envelope glycoprotein gp160 from HIV, 1 containing two non-covalently associated subunits, gp120 and gp41 (2), mediates the membrane fusion activity of the virus. The binding of the gp120 subunit to target cell receptors (3-7) induces a conformational change in the glycoprotein, which results in the exposure of a previously hidden hydrophobic N-terminal stretch of gp41, designated the "fusion peptide" (8, 9). Evidence supporting the role of the FP domain in mediating membrane fusion came from studies with intact envelope proteins (10 -12), as well as synthetic peptides used in model and biological systems (13-25). However, the molecular mechanism of membrane fusion is still poorly understood despite extensive studies done in both biological and model systems. Nevertheless, the results of many studies suggest common motifs for the diverse biological and model fusion reactions (13,26).Virus-induced membrane fusion is highly sensitive to single amino acid mutations in the FP domain (27,28). This can lead to the conclusion that the structure of FPs is a crucial parameter in the fusion process. Indeed, several studies suggest that the structure of FPs plays a major role in their activities (12,29). To distinguish between the effects of structure and hydrophobicity, we compared an all-L-amino acid FP with its enantiomer composed entirely of D-amino acids (25). Both had the same activity in liposome fusion assays, although having mirror image structures (25). Furthermore, the FP of HIV-1 was shown to inhibit cell-cell fusion (30 -32). Cumulative evidence suggests that the mechanism of inhibition is through interaction with the corresponding region in the intact gp41 (23,25). This inhibitory activity of the peptide is chirality-independent, eliminating the possibility of intera...

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Interaction of human immunodeficiency virus (HIV-1) fusion peptides with artificial lipid membranes

Cited by 42 publications

References 13 publications

Synthesis, Enhanced Fusogenicity, and Solid State NMR Measurements of Cross-Linked HIV-1 Fusion Peptides

Synthesis, Enhanced Fusogenicity, and Solid State NMR Measurements of Cross-Linked HIV-1 Fusion Peptides

A Peptide Derived from a Conserved Domain of Sendai Virus Fusion Protein Inhibits Virus-Cell Fusion

Inhibition of HIV-1 Envelope Glycoprotein-mediated Cell Fusion by a DL-Amino Acid-containing Fusion Peptide

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