SPC3, a V3 loop-derived synthetic peptide inhibitor of HIV-1 infection, binds to cell surface glycosphingolipids.
Synthetic multibranched peptides derived from the V3 domain of human immunodeficiency virus type 1 (HIV-1) gp120 inhibit HIV-1 entry into CD4+ and CD4- cells by two distinct mechanisms: competitive inhibition of HIV-1 binding to CD4-/GalCer+ colon cells and postbinding inhibition of HIV-1 fusion with CD4+ lymphocytes. In the present study, we have characterized the cellular binding sites for the V3 peptide SPC3, which possesses eight V3 consensus motifs GPGRAF radially branched on a neutral polyLys core matrix. These binding sites are glycosphingolipids that share a common structural determinant, i.e., a terminal galactose residue with a free hydroxyl group in position 4: GalCer/sulfatide on CD4-/GalCer+ colon cells; LacCer and its sialosyl derivatives GM3 and GD3 on CD4+ human lymphocytes. These data suggest that the V3 peptide binds to the GalCer/sulfatide receptor for HIV-1 gp120 on HT-29 cells and thus acts as a competitive inhibitor of virus binding to these CD4- cells, in full agreement with previously published virological data. In contrast, SPC3 does not bind to the CD4 receptor, in agreement with the data showing that the peptide inhibits HIV-1 infection of CD4+ cells by acting at a postattachment step. The binding of SPC3 to LacCer, GM3, and GD3, expressed by CD4+ lymphocytes, suggests a role for these glycosphingolipids in the fusion process between the viral envelope and the plasma membrane of CD4+ cells. Since the multivalent peptide can theoretically bind to several of these glycosphingolipids, we hypothesize that the resulting cross-linking of membrane components may affect the fluidity of the plasma membrane and/or membrane curvature, altering the virus-cell fusion mechanism.
Delézay
O
O
Laboratoire de Biochimie et Biologie de la Nutrition, URA-CNRS 1820, Faculté des Sciences de St Jérôme, Marseille, France.
Hammache
D
D
Fantini
J
J
Yahi
N
N
D000911:Antibodies, Monoclonal / Q000276:immunology / Q000378:metabolism; D015703:Antigens, CD; D000998:Antiviral Agents / Q000494:pharmacology; D001665:Binding Sites; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism; D002240:Carbohydrate Sequence; D002478:Cells, Cultured; D002855:Chromatography, Thin Layer; D005732:Gangliosides / Q000378:metabolism; D006028:Glycosphingolipids / Q000737:chemistry / Q000378:metabolism*; D015699:HIV Envelope Protein gp120 / Q000737:chemistry* / Q000378:metabolism* / Q000494:pharmacology; D015497:HIV-1 / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D007790:Lactosylceramides / Q000378:metabolism; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000737:chemistry* / Q000494:pharmacology*; D011994:Recombinant Proteins; D013433:Sulfoglycosphingolipids / Q000378:metabolism; D013498:Suramin / Q000494:pharmacology
D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D000998:Antiviral Agents; D005732:Gangliosides; D006028:Glycosphingolipids; D015699:HIV Envelope Protein gp120; C059762:HIV envelope protein gp120 (305-321); D007790:Lactosylceramides; D010446:Peptide Fragments; D011994:Recombinant Proteins; C098257:SPC3 peptide; D013433:Sulfoglycosphingolipids; C009744:CDw17 antigen; D013498:Suramin