HTLV-1 uses HSPG and neuropilin-1 for entry by molecular mimicry of VEGF165.
Human T-cell lymphotropic virus type 1 (HTLV-1) entry involves the interaction between the surface (SU) subunit of the Env proteins and cellular receptor(s). Previously, our laboratories demonstrated that heparan sulfate proteoglycans (HSPGs) and neuropilin-1 (NRP-1), a receptor of VEGF(165), are essential for HTLV-1 entry. Here we investigated whether, as when binding VEGF(165), HSPGs and NRP-1 work in concert during HTLV-1 entry. VEGF(165) binds to the b domain of NRP-1 through both HSPG-dependent and -independent interactions, the latter involving its exon 8. We show that VEGF(165) is a selective competitor of HTLV-1 entry and that HTLV-1 mimics VEGF(165) to recruit HSPGs and NRP-1: (1) the NRP-1 b domain is required for HTLV-1 binding; (2) SU binding to target cells is blocked by the HSPG-binding domain of VEGF(165); (3) the formation of Env/NRP-1 complexes is enhanced by HSPGs; and (4) the HTLV SU contains a motif homologous to VEGF(165) exon 8. This motif directly binds to NRP-1 and is essential for HTLV-1 binding to, internalization into, and infection of CD4(+) T cells and dendritic cells. These findings demonstrate that HSPGs and NRP-1 function as HTLV-1 receptors in a cooperative manner and reveal an unexpected mimicry mechanism that may have major implications in vivo.
Lambert
Sophie
S
Centre National de la Recherche Scientifique Unite Mixte de Recherche , Inserm U, Université Paris-Descartes, Institut Cochin, France.
Bouttier
Manuella
M
Vassy
Roger
R
Seigneuret
Michel
M
Petrow-Sadowski
Cari
C
Janvier
Sébastien
S
Heveker
Nikolaus
N
Ruscetti
Francis W
FW
Perret
Gérard
G
Jones
Kathryn S
KS
Pique
Claudine
C
D001667:Binding, Competitive; D002478:Cells, Cultured; D015686:Gene Products, env / Q000378:metabolism; D015490:HTLV-I Infections / Q000821:virology; D019812:Heparan Sulfate Proteoglycans / Q000378:metabolism*; D015368:Human T-lymphotropic virus 1 / Q000472:pathogenicity*; D006801:Humans; D018716:Molecular Mimicry; D039942:Neuropilin-1 / Q000378:metabolism*; D011485:Protein Binding; D011991:Receptors, Virus / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*; D053585:Virus Attachment
D015686:Gene Products, env; D019812:Heparan Sulfate Proteoglycans; D011991:Receptors, Virus; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D039942:Neuropilin-1