A CD4-Independent interaction of human immunodeficiency virus-1 gp120 withCXCR4 induces their cointernalization, cell signaling, and T-cell chemotaxis

The gp120 envelope glycoprotein of human immunodeficiency virus-1 (HIV-1) i nteracts with the CXCR4 chemokine receptor, but it is not known whether gp1 20 activates CXCR4-mediated signaling cascades in the same manner as its na tural ligand, SDF1 alpha. 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 condition s, the interaction of CXCR4 and gp120 resulted in their CD4-independent coi nternalization. Both molecules were translocated into early endosomes, wher eas neither protein could be detected in late endosomes. Binding of gp120 t o CXCR4 resulted in a CD4-independent phosphorylation of Pyk2 and an induct ion of chemotactic activity, demonstrating that this interaction has functi onal consequences. Interestingly, however, whereas SDF1 alpha activated the ERK/MAP kinase pathway, this cascade was not induced by gp120. Together, t hese results suggest that the pathology of HIV-1 infection may be modulated by the distinct signal transduction pathway mediated by gp120 upon its int eraction with CXCR4. (C) 1999 by The American Society of Hematology.