Induction of phosphorylation and intracellular association of CC chemokine receptor 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 transduces intracellular signals through the primary envelope receptor, CD4, and/or the envelope coreceptor, a seven-transmembrane chemokine receptor. Macrophage-tropic strains of HIV-1 preferentially use CCR5 as an entry coreceptor, whereas T cell-tropic strains use CXC chemokine receptor-4 for entry. Intracellular signals transduced by HIV-1 envelope may have immunopathogenic consequences, including anergy, syncytium formation, apoptosis, and inappropriate cell trafficking. We demonstrate here that a recombinant envelope protein derived from an M-tropic isolate of HIV-1 can transduce CD4-dependent as well as CCR5-dependent intracellular signals in primary human CD4+ T cells. Novel HIV-induced intracellular signals that were identified include tyrosine phosphorylation of focal adhesion kinase (FAK) and CCR5, which are involved in cell adhesion and chemotaxis, respectively. HIV envelope-induced cellular association of FAK and CCR5 was also demonstrated, suggesting that ligation of CD4 and CCR5 leads to the formation of an activation complex composed of FAK and CCR5. Activation of this signaling pathway by HIV-1 envelope may be an important pathogenic mechanism of dysregulated cellular activation and trafficking during HIV infection.
Cicala
C
C
Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, Bethesda, MD 20892, USA. ccicala@nih.gov
Arthos
J
J
Ruiz
M
M
Vaccarezza
M
M
Rubbert
A
A
Riva
A
A
Wildt
K
K
Cohen
O
O
Fauci
A S
AS
D015704:CD4 Antigens / Q000276:immunology / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000201:enzymology / Q000378:metabolism* / Q000821:virology; D015815:Cell Adhesion Molecules / Q000378:metabolism*; D002449:Cell Aggregation / Q000276:immunology; D002460:Cell Line; D051417:Focal Adhesion Kinase 1; D051416:Focal Adhesion Protein-Tyrosine Kinases; D015686:Gene Products, env / Q000502:physiology*; D006678:HIV / Q000502:physiology*; D006801:Humans; D007424:Intracellular Fluid / Q000276:immunology / Q000378:metabolism*; D008024:Ligands; D008264:Macrophages / Q000821:virology*; D010750:Phosphoproteins / Q000378:metabolism; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D019713:Receptors, CCR5 / Q000276:immunology / Q000378:metabolism*; D015398:Signal Transduction / Q000276:immunology; D014443:Tyrosine / Q000378:metabolism
D015704:CD4 Antigens; D015815:Cell Adhesion Molecules; D015686:Gene Products, env; D008024:Ligands; D010750:Phosphoproteins; D019713:Receptors, CCR5; D014443:Tyrosine; D011505:Protein-Tyrosine Kinases; D051417:Focal Adhesion Kinase 1; D051416:Focal Adhesion Protein-Tyrosine Kinases; C496050:PTK2 protein, human