A CD4-independent interaction of human immunodeficiency virus-1 gp120 with CXCR4 induces their cointernalization, cell signaling, and T-cell chemotaxis.
The gp120 envelope glycoprotein of human immunodeficiency virus-1 (HIV-1) interacts with the CXCR4 chemokine receptor, but it is not known whether gp120 activates CXCR4-mediated signaling cascades in the same manner as its natural ligand, SDF1alpha. We assessed the effects of wild-type gp120 and a mutant gp120 that interacts with CXCR4 but not CD4 on CD4(-)/CXCR4(+) cells and CD4(+)/CXCR4(+) cells, respectively. Under both experimental conditions, the interaction of CXCR4 and gp120 resulted in their CD4-independent cointernalization. Both molecules were translocated into early endosomes, whereas neither protein could be detected in late endosomes. Binding of gp120 to CXCR4 resulted in a CD4-independent phosphorylation of Pyk2 and an induction of chemotactic activity, demonstrating that this interaction has functional consequences. Interestingly, however, whereas SDF1alpha activated the ERK/MAP kinase pathway, this cascade was not induced by gp120. Together, these results suggest that the pathology of HIV-1 infection may be modulated by the distinct signal transduction pathway mediated by gp120 upon its interaction with CXCR4.
Missé
D
D
Laboratoire d'Immunologie Rétrovirale et Moléculaire, Institut de Recherches pour le Développement, Montpellier, France.
Cerutti
M
M
Noraz
N
N
Jourdan
P
P
Favero
J
J
Devauchelle
G
G
Yssel
H
H
Taylor
N
N
Veas
F
F
D015703:Antigens, CD / Q000502:physiology*; D015704:CD4 Antigens / Q000502:physiology*; D002462:Cell Membrane / Q000502:physiology / Q000648:ultrastructure / Q000821:virology; D002634:Chemotaxis, Leukocyte; D011992:Endosomes / Q000502:physiology / Q000821:virology; D005434:Flow Cytometry; D015699:HIV Envelope Protein gp120 / Q000378:metabolism*; D015497:HIV-1 / Q000502:physiology*; D006801:Humans; D019169:Jurkat Cells; D019718:Receptors, CXCR4 / Q000502:physiology*; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000276:immunology / Q000502:physiology* / Q000821:virology
D015703:Antigens, CD; D015704:CD4 Antigens; D015699:HIV Envelope Protein gp120; D019718:Receptors, CXCR4