The CXCR4 antagonist AMD3100 efficiently inhibits cell-surface-expressed human immunodeficiency virus type 1 envelope-induced apoptosis

Infection by human immunodeficiency virus type 1 (HIV-1) has been associate d with increased cell death by apoptosis in infected and uninfected cells. The envelope glycoprotein complex ([gp120/gp41](n)) of X4 HIV-1 isolates is involved in both infected and uninfected cell death via its interaction wi th cellular receptors CD4 and CXCR4. We studied the effect of the blockade of CXCR4 receptors by the agonist stromal derived factor (SDF-1 alpha) and the antagonist bicyclam AMD3100 on apoptotic cell death of CD4(+) cells in different models of HIV infection. In HIV-infected CEM or SUP-T1 cultures, AMD3100 showed antiapoptotic activity even when added 24 h after infection. In contrast, other antiviral agents, such as zidovudine, failed to block a poptosis under these conditions. The antiapoptotic activity of AMD3100 was also studied in coculture of peripheral blood mononuclear cells or CD4(+) c ell lines with chronically infected H9/IIIB cells. AMD3100 was found to inh ibit both syncytium formation and apoptosis induction with 50% inhibitory c oncentrations ranging from 0.009 to 0.24 mu g/ml, depending on the cell typ e. When compared to SDF-1 alpha, AMD3100 showed higher inhibitory potency i n all cell lines tested. Our data indicate that the bicyclam AMD3100 not on ly inhibits HIV replication but also efficiently blocks cell-surface-expres sed HIV-1 envelope-induced apoptosis in uninfected cells.