Induction of phosphorylation and intracellular association of CC chemokinereceptor 5 and focal adhesion kinase in primary human CD4(+) T cells by macrophage-tropic HIV envelope

Binding of HIV-1 envelope glycoproteins to the surface of a CD4(+) cell tra nsduces intracellular signals through the primary envelope receptor, CD4, a nd/or the envelope coreceptor, a seven-transmembrane chemokine receptor. Ma crophage-tropic strains of HIV-1 preferentially use CCR5 as an entry corece ptor, whereas T cell-tropic strains use CXC chemokine receptor-4 for entry. Intracellular signals transduced by HIV-1 envelope may have immunopathogen ic consequences, including anergy, syncytium formation, apoptosis, and inap propriate cell trafficking, We demonstrate here that a recombinant envelope protein derived from an M-tropic isolate of HIV-1 can transduce CD4-depend ent as well as CCR5-dependent intracellular signals in primary human CD4(+) T cells. Novel HIV-induced intracellular signals that were identified incl ude tyrosine phosphorylation of focal adhesion kinase (FAK) and CCR5, which are involved in cell adhesion and chemotaxis, respectively. HIV envelope-i nduced cellular association of FAK and CCR5 was also demonstrated, suggesti ng that ligation of CD4 and CCR5 leads to the formation of an activation co mplex composed of FAK and CCR5, Activation of this signaling pathway by HIV -1 envelope may be an important pathogenic mechanism of dysregulated cellul ar activation and trafficking during HIV infection.