A highly conserved arginine in gp120 governs HIV-1 binding to both syndecans and CCR5 via sulfated motifs.
HIV-1 has maximized its utilization of syndecans. It uses them as in cis receptors to infect macrophages and as in trans receptors to infect T-lymphocytes. In this study, we investigated at a molecular level the mechanisms that control HIV-1-syndecan interactions. We found that a single conserved arginine (Arg-298) in the V3 region of gp120 governs HIV-1 binding to syndecans. We found that an amine group on the side chain of this residue is necessary for syndecan utilization by HIV-1. Furthermore, we showed that HIV-1 binds syndecans via a 6-O sulfation, demonstrating that this binding is not the result of random interactions between basic residues and negative charges, but the result of specific contacts between gp120 and a well defined sulfation in syndecans. Surprisingly, we found that Arg-298, which mediates HIV-1 binding to syndecans, also mediates HIV-1 binding to CCR5. We postulated that HIV-1 recognizes similar motifs on syndecans and CCR5. Supporting this hypothesis, we obtained several lines of evidence that suggest that the 6-O sulfation recognized by HIV-1 on syndecans mimics the sulfated tyrosines recognized by HIV-1 in the N terminus of CCR5. Our finding that CCR5 and syndecans are exploited by HIV-1 via a single determinant echoes the mechanisms by which chemokines utilize these two disparate receptors and suggests that the gp120/chemokine mimicry may represent a common strategy in microbial pathogenesis.
de Parseval
Aymeric
A
Department of Immunology, The Scripps Research Institute, La Jolla, California 92037, USA.
Bobardt
Michael D
MD
Chatterji
Anju
A
Chatterji
Udayan
U
Elder
John H
JH
David
Guido
G
Zolla-Pazner
Susan
S
Farzan
Michael
M
Lee
Tun-Hou
TH
Gallay
Philippe A
PA
D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D001120:Arginine / Q000737:chemistry; D001665:Binding Sites; D002460:Cell Line; D017124:Conserved Sequence; D015699:HIV Envelope Protein gp120 / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D015497:HIV-1 / Q000235:genetics / Q000378:metabolism* / Q000472:pathogenicity; D006801:Humans; D008562:Membrane Glycoproteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D008954:Models, Biological; D018716:Molecular Mimicry; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D011509:Proteoglycans / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D019713:Receptors, CCR5 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D013431:Sulfates / Q000737:chemistry; D053667:Syndecans
D015699:HIV Envelope Protein gp120; C059762:HIV envelope protein gp120 (305-321); D008562:Membrane Glycoproteins; D010446:Peptide Fragments; D011509:Proteoglycans; D019713:Receptors, CCR5; D011993:Recombinant Fusion Proteins; D013431:Sulfates; D053667:Syndecans; D001120:Arginine