HUMAN-IMMUNODEFICIENCY-VIRUS-1 ENVELOPE-INITIATED G(2)-PHASE PROGRAMMED CELL-DEATH

Despite intensive investigation, no clearly defined mechanism explaini ng human immunodeficiency virus (HIV)-induced cell killing has emerged . HIV-1 infection is initiated through a high-affinity interaction bet ween the HIV-1 external envelope glycoprotein (gp120) and the CD4 rece ptor on T cells. Cell killing is a later event intimately linked by in vitro genetic analyses with the fusogenic properties of the HIV envel ope glycoprotein gp120 and transmembrane glycoprotein gp41. In this re port, we describe aberrancies in cell cycle regulatory proteins initia ted by cell-cell contact between T cells expressing HIV-1 envelope gly coproteins and other T cells expressing CD4 receptors. Cells rapidly a ccumulate cyclin B protein and tyrosine-hyperphosphorylated p34cdc2 (c dk1) kinase, indicative of cell cycle arrest at G(2) phase. Moreover, these cells continue to synthesize cyclin B protein, enlarge and displ ay an abnormal ballooned morphology, and disappear from the cultures i n a pattern previously described for cytoxicity induced by DNA synthes is (S phase) inhibitors. Similar changes are observed in peripheral bl ood mononuclear cells infected in vitro with pathogenic primary isolat es of HIV-1.