gp120-mediated induction of the MAPK cascade is dependent on the activation state of CD4(+) lymphocytes

Kinet, S.; Bernard, F.; Mongellaz, C.; Perreau, M.; Goldman, F. D.; Taylor, N.


2002-10-01 / vol 100 / pages 2546-53


The capacity of the HIV-1 envelope glycoprotein gp120 to induce intracellular signals is thought to contribute to HIV-1 pathogenesis. Here, we report that gp120 binding resulted in activation of the mitogen-activated protein kinase (MAPK) in CD4(+) lymphocytes prestimulated through their T-cell receptor (TCR). However, gp120 did not activate this pathway in either freshly isolated quiescent T cells or nonproliferating CD4(+) lymphocytes prestimulated with the interleukin-7 (IL-7) cytokine. This response was not solely dependent on proliferation per se because proliferating IL-7-prestimulated umbilical cord (UC)-derived T lymphocytes did not exhibit significant MAPK activation upon gp120 binding. Nevertheless, like peripheral blood lymphocytes, MAPK recruitment was induced by gp120 in UC T cells following TCR prestimulation. The lack of a gp120-mediated signaling response was not due to decreased gp120 receptor levels; CD4 expression was modified neither by IL-7 nor by TCR engagement, and high levels of functional CXCR4 were present on IL-7-treated lymphocytes. In addition to CD4 and CXCR4, recent evidence suggests that glycosphingolipids in raft microdomains serve as cofactors for HIV-1 fusion. The ganglioside GM1, a marker of rafts, was augmented in TCR-stimulated but not IL-7-stimulated T lymphocytes, and disruption of rafts inhibited gp120-induced signaling. Thus, stimulation of a mitogenic pathway by gp120 appears to require receptor binding in the context of membrane microdomains. These studies reveal a mechanism via which gp120 may differentially modulate the fate of activated and quiescent T cells in vivo.

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Humans; Cells, Cultured; Cell Line, Transformed; Receptors, Antigen, T-Cell/immunology; Adult; Lymphocyte Activation/*immunology; Cell Cycle/physiology; Jurkat Cells; CD4-Positive T-Lymphocytes/cytology/drug effects/*immunology; HIV Envelope Protein gp120/*pharmacology; HIV-1/*immunology; MAP Kinase Signaling System/*physiology

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