CXCR4 AND CD4 MEDIATE A RAPID CD95-INDEPENDENT CELL-DEATH IN CD4(-CELLS() T)

AIDS is characterized by a progressive decrease of CD4(+) helper T lym phocytes. Destruction of these cells may invoice programmed cell death , apoptosis. It has previously been reported that apoptosis can be ind uced even in noninfected cells by HIV-1 gp120 and anti-gp120 antibodie s. HIV-1 gp120 binds to T cells via CD4 and the chemokine coreceptor C XCR4 (fusin/LESTR). Therefore, we investigated whether CD4 and CXCR4 m ediate gp120-induced apoptosis. We used human peripheral blood lymphoc ytes, malignant T cells, and CD4/CXCR4 transfectants, and found cell d eath induced by both cell surface receptors, CD I and CXCR4. The induc ed cell death was rapid, independent of known caspases, and lacking ol igonucleosomal DNA fragmentation, In addition, the death signals were not propagated via p56(lck) and G(i)alpha, However, the cells showed c hromatin condensation, morphological shrinkage, membrane inversion, an d reduced mitochondrial transmembrane potential indicative of apoptosi s, Significantly, apoptosis was exclusively observed in CD4(+) but not in CD8(+) T cells, and apoptosis triggered via CXCR4 was inhibited by stromal cell-derived factor-1, the natural CXCR4 ligand. Thus, this m echanism of apoptosis might contribute to T cell depletion in AIDS and might have major implications for therapeutic intervention.