Human T-cell lymphotropic virus type 1 (HTLV-1) is transmitted through a viral synapse and enters target cells via interaction with the glucose transporter GLUT1. Here, we show that Neuropilin-1 (NRP1), the receptor for semaphorin-3A and VEGF-A165 and a member of the immune synapse, is also a physical and functional partner of HTLV-1 envelope (Env) proteins. HTLV-1 Env and NRP1 complexes are formed in cotransfected cells, and endogenous NRP1 contributes to the binding of HTLV-1 Env to target cells. NRP1 overexpression increases HTLV-1 Env-dependent syncytium formation. Moreover, overexpression of NRP1 increases both HTLV-1 and HTLV-2 Env-dependent infection, whereas down-regulation of endogenous NRP1 has the opposite effect. Finally, overexpressed GLUT1, NRP1, and Env form ternary complexes in transfected cells, and endogenous NRP1 and GLUT1 colocalize in membrane junctions formed between uninfected and HTLV-1-infected T cells. These data show that NRP1 is involved in HTLV-1 and HTLV-2 entry, suggesting that the HTLV receptor has a multicomponent nature.Human T-cell lymphotropic virus type 1 (HTLV-1) causes adult T-cell leukemia/lymphoma and HTLV-1-associated myelopathy/tropical spastic paraparesis (49). Unlike other retroviruses, free HTLV-1 virions are poorly infectious, with cellto-cell contact being the major route of viral transfer in vivo (14). The importance of intercellular contacts for efficient HTLV-1 transmission was highlighted by Bangham and collaborators, who showed that an essential determinant of HTLV-1 cell-cell spreading is the establishment of a viral synapse (21).On the viral side, HTLV-1 entry depends on the 46-kDa surface glycoprotein (SU), which is responsible for receptor recognition, and the 21-kDa transmembrane glycoprotein (TM), which triggers the fusion between viral and cellular membranes (32). Both proteins are produced by cleavage of the 61-kDa envelope (Env) precursor (42,46). Regions in the 313-amino-acid-long SU encompassing residues 100 and 200 were shown to be the targets of neutralizing antibodies (2,43,57). Consistent with these observations, we and others showed that mutations introduced in these regions reduce the ability of HTLV-1 Env to trigger syncytium formation and/or virus infection (11,12,48,52,59).Originally detected in CD4 ϩ T cells (50), HTLV-1 infects other cell types in vivo, including CD8 ϩ T cells, monocytes, endothelial cells, and dendritic cells (18,20,30,33). In contrast to this limited tropism in vivo, the HTLV receptor appears to be expressed in almost all cell lines. Moreover, the HTLV receptor is highly conserved in vertebrate species (41, 56). As a result of Env/receptor interactions, the HTLV-1 receptor is down-regulated or nonfunctional at the surface of chronically infected T cells (17,47). Cell fusion induced by HTLV-2, a closely related nonpathogenic retrovirus, is also prevented in chronically HTLV-1-infected T cells, demonstrating that HTLV-1 and HTLV-2 share the same receptor (55). Heparan sulfate proteoglycans have been reported to play a rol...

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