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Prepublished online as a Blood First Edition Paper on May 13, 2002; DOI 10.1182/blood-2002-03-0819.
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Blood, 1 October 2002, Vol. 100, No. 7, pp. 2546-2553
IMMUNOBIOLOGY
gp120-mediated induction of the MAPK cascade is dependent on the
activation state of CD4+ lymphocytes
Sandrina Kinet,
Fréderic Bernard,
Cédric Mongellaz,
Matthieu Perreau,
Frederick D. Goldman, and
Naomi Taylor
From the Institut de Génétique
Moléculaire de Montpellier, Centre National de Recherche
Scientifique (CNRS) UMR 5535/IFR 22, Montpellier, France; and
University of Iowa Hospitals and Clinics, Iowa City,
IA.
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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