title: Inhibition of coreceptor-independent cell-to-cell human immunodeficiency virus type 1 transmission by a CD4-immunoglobulin G2 fusion protein.
abstract: We have previously shown (J. Blanco et al., J. Biol. Chem. 279:51305-51314, 2004) that the contact between HIV producing cells and primary CD4(+) T cells may induce the uptake of human immunodeficiency virus (HIV) particles by target cells in the absence of HIV envelope-mediated membrane fusion or productive HIV replication. HIV uptake by CD4(+) T cells was dependent on cellular contacts mediated by the binding of gp120 to CD4 but was independent of the expression of the appropriate HIV coreceptor, CCR5 or CXCR4. Here, we have characterized the effect of agents blocking gp120 binding to CD4 on cell-to-cell HIV transmission. A recombinant CD4-based protein (CD4-immunoglobulin G2 [IgG2]), that is currently being evaluated in clinical trials, completely inhibited the uptake of HIV particles by CD4(+) T cells from persistently infected cells expressing R5, X4, or X4/T-20-resistant HIV-1 envelope glycoproteins. Consequently, both the release of viral particles from endocytic vesicles and the infection of reporter U87-CD4 cells were also prevented. The polyanionic anti-HIV agent dextran sulfate failed to prevent the intracellular uptake of virions by CD4(+) T cells. Indeed, it increased HIV uptake in a dose-dependent manner, suggesting functional differences between the specific gp120-targeting CD4-IgG2 agent and nonspecific HIV binding inhibitors. Thus, the inhibition of the specific interaction between gp120 and CD4 protein could be an effective strategy to inhibit HIV binding to CD4(+) T cells, and the mechanism by which CD4(+) T cells lacking the appropriate coreceptor may be converted in HIV carriers.
authors.affiliation: Retrovirology Laboratory irsiCaixa, Hospital Universitari Germans Trias i Pujol, Universitat Autònoma de Barcelona, Badalona, Spain.
authors.forename: Berta
authors.initials: B
authors.lastname: Bosch
authors.forename: Julià
authors.initials: J
authors.lastname: Blanco
authors.forename: Eduardo
authors.initials: E
authors.lastname: Pauls
authors.forename: Imma
authors.initials: I
authors.lastname: Clotet-Codina
authors.forename: Mercedes
authors.initials: M
authors.lastname: Armand-Ugón
authors.forename: Boyan
authors.initials: B
authors.lastname: Grigorov
authors.forename: Delphine
authors.initials: D
authors.lastname: Muriaux
authors.forename: Bonaventura
authors.initials: B
authors.lastname: Clotet
authors.forename: Jean-Luc
authors.initials: JL
authors.lastname: Darlix
authors.forename: José A
authors.initials: JA
authors.lastname: Esté
mesh_terms: D015704:CD4 Antigens / Q000378:metabolism*; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism*; D002460:Cell Line; D002478:Cells, Cultured; D018920:Coculture Techniques; D015658:HIV Infections / Q000635:transmission*; D015497:HIV-1 / Q000378:metabolism*; D006801:Humans; D007074:Immunoglobulin G / Q000235:genetics / Q000378:metabolism*; D007963:Leukocytes, Mononuclear / Q000378:metabolism / Q000821:virology; D019713:Receptors, CCR5 / Q000378:metabolism; D019718:Receptors, CXCR4 / Q000378:metabolism; D015728:Receptors, HIV / Q000037:antagonists & inhibitors*; D011993:Recombinant Fusion Proteins / Q000378:metabolism
chemical_list: D015704:CD4 Antigens; D007074:Immunoglobulin G; D019713:Receptors, CCR5; D019718:Receptors, CXCR4; D015728:Receptors, HIV; D011993:Recombinant Fusion Proteins