Inhibition of tyrosine kinase activation blocks the down-regulation of CXC chemokine receptor 4 by HIV-1 gp120 in CD4+ T cells.
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-1alpha (SDF-1alpha), accompanied by a markedly reduced surface expression of CXCR4. gp120, but not SDF-1alpha, induced rapid tyrosine phosphorylation of src-like kinase p56lck in CD4+ T cells, whereas both gp120 and SDF-1alpha 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-1alpha. Thus, a CD4-associated signaling molecule(s) including p56lck is activated by gp120 and is required for the down-regulation of CXCR4.
Su
S B
SB
Laboratory of Molecular Immunoregulation, Division of Basic Sciences, SAIC-Frederick National Cancer Institute, MD 21702, USA.
Gong
W
W
Grimm
M
M
Utsunomiya
I
I
Sargeant
R
R
Oppenheim
J J
JJ
Ming Wang
J
J
D016227:Benzoquinones; D015704:CD4 Antigens / Q000502:physiology; D015496:CD4-Positive T-Lymphocytes / Q000201:enzymology* / Q000378:metabolism / Q000502:physiology; D002464:Cell Migration Inhibition; D002478:Cells, Cultured; D002634:Chemotaxis, Leukocyte / Q000187:drug effects; D015536:Down-Regulation / Q000187:drug effects / Q000276:immunology*; D004789:Enzyme Activation / Q000187:drug effects / Q000276:immunology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005434:Flow Cytometry; D015699:HIV Envelope Protein gp120 / Q000235:genetics / Q000494:pharmacology*; D015497:HIV-1 / Q000276:immunology*; D006801:Humans; D047029:Lactams, Macrocyclic; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck) / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011809:Quinones / Q000494:pharmacology; D019718:Receptors, CXCR4 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011994:Recombinant Proteins / Q000494:pharmacology; D017828:Rifabutin / Q000031:analogs & derivatives; D014407:Tumor Cells, Cultured
D016227:Benzoquinones; D015704:CD4 Antigens; D004791:Enzyme Inhibitors; D015699:HIV Envelope Protein gp120; D047029:Lactams, Macrocyclic; D011809:Quinones; D019718:Receptors, CXCR4; D011994:Recombinant Proteins; D017828:Rifabutin; C020754:herbimycin; D011505:Protein-Tyrosine Kinases; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck)