Inhibition of tyrosine kinase activation blocks the down-regulation of CXCchemokine receptor 4 by HIV-1 gp120 in CD4(+) T cells

Because the binding of HIV-1 envelope to CD4 initiates a cofigurational cha nge in glycoprotein 120 (gp120), enabling it to interact with fusion corece ptors, we investigated how this process interferes with the expression and function of CXC chemokine receptor 4 (CXCR4) in CD4(+) T lymphocytes, A rec ombinant gp120 (MN), after preincubation with CD4(+) T lymphocytes, signifi cantly inhibited the binding and chemotaxis of the cells in response to the CXCR4 ligand stromal cell-derived factor-1 alpha (SDF-1 alpha), accompanie d by a markedly reduced surface expression of CXCR4, gp120, but not SDF-1 a lpha, induced rapid tyrosine phosphorylation of src-like kinase p56(lck) in CD4(+) T cells, whereas both gp120 and SDF-1 alpha caused phosphorylation of the CXCR4, The tyrosine kinase inhibitor herbimycin A abolished the phos phorylation of p56(lck) and CXCR4 induced by gp120 in association with main tenance of normal expression of cell surface CXCR4 and a migratory response to SDF-1 alpha, Thus, a CD4-associated signaling molecule(s) including p56 (lck) is activated by gp120 and is required for the down-regulation of CXCR 4.