gp120-mediated induction of the MAPK cascade is dependent on the activation state of CD4(+) lymphocytes.
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.
Kinet
Sandrina
S
Institut de Génétique Moléculaire de Montpellier, Centre National de Recherche Scientifique (CNRS) UMR 5535/IFR 22, Montpellier, France.
Bernard
Fréderic
F
Mongellaz
Cédric
C
Perreau
Matthieu
M
Goldman
Frederick D
FD
Taylor
Naomi
N
D000328:Adult; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000187:drug effects / Q000276:immunology*; D002453:Cell Cycle / Q000502:physiology; D002461:Cell Line, Transformed; D002478:Cells, Cultured; D015699:HIV Envelope Protein gp120 / Q000494:pharmacology*; D015497:HIV-1 / Q000276:immunology*; D006801:Humans; D019169:Jurkat Cells; D008213:Lymphocyte Activation / Q000276:immunology*; D020935:MAP Kinase Signaling System / Q000502:physiology*; D011948:Receptors, Antigen, T-Cell / Q000276:immunology
D015699:HIV Envelope Protein gp120; D011948:Receptors, Antigen, T-Cell