The implication of the chemokine receptor CXCR4 in HIV-1 envelope protein-induced apoptosis is independent of the G protein-mediated signalling

Objective: The envelope glycoprotein complex (gp120/gp41)(n) of HIV-1 is on e of the viral products responsible far increased apoptosis in HIV infectio n. Here the role of the chemokine receptor CXCR4 in HIV-1 envelope protein- induced apoptosis was investigated. Methods: Apoptosis occurring in cocultures of chronically HIV-1 IIIB-infect ed cells with CD4 target cells expressing the CXCR4 receptor was quantified by terminal deoxinucleotidyl transferase dUTP nick end labeling (TUNEL) or propidium iodide staining followed by fluorescent antibody cell sorting, w hich allows the evaluation of single-cell killing. Moreover global (single cell- and syncytium-associated) apoptosis was quantified by a new radioacti ve TUNEL-derived assay. Results: By using these different techniques it was shown that single and s yncytium-forming CD4 T cells die by apoptosis upon contact with envelope pr otein expressing cells independently of viral replication. Moreover, both t he CXCR4 agonist SDF-1 alpha, and the antagonist AMD3100, showed inhibitory effects on HIV-1 envelope protein-induced apoptosis in the CD4 T-cell subs et of peripheral blood mononuclear cells and CD4 cell lines. CXCR4 signalli ng-induced by HIV-1 envelope proteins in CD4 T cells was not detected. Furt hermore, it was shown that envelope protein-induced apoptosis can occur aft er treating target cells with the Gi-protein inhibitor pertussis toxin. Conclusions: Evidence is provided for a role of CXCR4 in the mechanisms of HIV envelope protein-induced pathogenesis, contributing to selective CD4 ce ll killing. The results suggest that CXCR4 is involved in HIV-1-induced apo ptosis; however, this role does not appear to involve G-protein-mediated CX CR4 signalling. (C) 1999 Lippincott Williams & Wilkins.