HIV-1 gp41 envelope residues 650-685 exposed on native virus act as a lectin to bind epithelial cell galactosyl ceramide.
The initial step in the interaction between human immunodeficiency virus (HIV-1) and epithelial cells is the binding of HIV-1 envelope glycoproteins to the epithelial cell galactosyl ceramide (GalCer). Here we show that HIV-1 envelope gp41 residues 650-685 bind GalCer in a galactose-specific manner. The gp41 residues that display this lectin activity are highly conserved among HIV-1 isolates and constitute three regions: residues 650-661, which encompass a charged helix; residues 662-667, referred to as the conserved epitope ELDKWA, the epitope recognized by antibodies that neutralize HIV-1 entry in epithelial and CD4(+)-mononucleated cells; and residues 668-685, a hydrophobic Trp-rich sequence that stabilizes the structure of the galactose binding site. Similar to other galactose-specific lectins, the gp41 lectin site is active only as an oligomer. Finally the orientation of the galactose toward the gp41 lectin site appears to be controlled by the lipid microenvironment of the epithelial membrane. From the experimental data we construct a theoretical model of the interaction between gp41 and GalCer based on thermodynamic considerations. This model integrates the dynamics and the spatial organization of the viral envelope glycoproteins, GalCer organized in raft microdomains in the apical region of the epithelial cell membrane and the interfacial water. Characterization of the minimal sequence and structure of gp41 in direct interaction with GalCer may help unravel the still unknown immunogenic determinant able to elicit antibodies against ELDKWA and target of one of the rare neutralizing antibodies against gp41.
Alfsen
Annette
A
Entrée Muqueuse du VIH et Immunité Muqueuse, Departement de Biologie Cellulaire, Institut Cochin, 22 rue Mechain, 75014 Paris, France.
Bomsel
Morgane
M
D002942:Circular Dichroism; D004847:Epithelial Cells / Q000378:metabolism; D005699:Galactosylceramides / Q000378:metabolism*; D015700:HIV Envelope Protein gp41 / Q000737:chemistry / Q000378:metabolism*; D015497:HIV-1 / Q000378:metabolism*; D019073:HT29 Cells; D006801:Humans; D037102:Lectins / Q000378:metabolism*; D011485:Protein Binding; D013050:Spectrometry, Fluorescence; D013816:Thermodynamics
D005699:Galactosylceramides; D015700:HIV Envelope Protein gp41; D037102:Lectins