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Prepublished online as a Blood First Edition Paper on May 13, 2002; DOI 10.1182/blood-2002-03-0819.
Submitted March 14, 2002
Accepted May 3, 2002
gp120-mediated induction of the MAPK cascade is dependent on the activation state of CD4+ lymphocytes and raft integrity
Sandrina Kinet, Frederic Bernard, Cedric Mongellaz, Matthieu Perreau, Frederick Goldman, and Naomi Taylor*
Institut de Genetique Moleculaire de Montpellier, Montepellier Cedex 05, France
Dept of Pediatrics, University of Iowa, Iowa City, IA, USA
* Corresponding author; email: taylor{at}igm.cnrs-mop.fr.
The capacity of the SUgp120 HIV-1 envelope glycoprotein 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 TCR. However, gp120 did not activate this pathway in either freshly isolated quiescent T cells or non-proliferating CD4+ lymphocytes prestimulated with the IL-7 cytokine. This response was not solely dependent on proliferation per se since proliferating IL-7-prestimulated umbilical cord (UC)-derived T lymphocytes did not exhibit 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 also 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- but not IL-7-stimulated T lymphocytes and disruption of rafts inhibited gp120-induced signaling. Thus, stimulation of a mitogenic pathway by gp120 requires 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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