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*
Laboratory of Molecular Immunoregulation, Division of Basic Sciences,
SAIC-Frederick National Cancer Institute, Frederick Cancer Research and Development Center, Frederick, MD 21702; and
Millenium Biotechnology, Ramona, CA 92065
Because the binding of HIV-1 envelope to CD4 initiates a
configurational change in glycoprotein 120 (gp120), enabling it to
interact with fusion coreceptors, we investigated how this process
interferes with the expression and function of CXC chemokine receptor 4
(CXCR4) in CD4+ T lymphocytes. A recombinant gp120 (MN),
after preincubation with CD4+ T lymphocytes, significantly
inhibited the binding and chemotaxis of the cells in response to the
CXCR4 ligand stromal cell-derived factor-1
(SDF-1), accompanied
by a markedly reduced surface expression of CXCR4. gp120, but not
SDF-1, induced rapid tyrosine phosphorylation of src-like kinase
p56lck in CD4+ T cells,
whereas both gp120 and SDF-1 caused phosphorylation of the CXCR4.
The tyrosine kinase inhibitor herbimycin A abolished the
phosphorylation of p56lck and CXCR4 induced by
gp120 in association with maintenance of normal expression of cell
surface CXCR4 and a migratory response to SDF-1. Thus, a
CD4-associated signaling molecule(s) including
p56lck is activated by gp120 and is required
for the down-regulation of CXCR4.
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