title: HIV gp41-induced apoptosis is mediated by caspase-3-dependent mitochondrial depolarization, which is inhibited by HIV protease inhibitor nelfinavir.
abstract: Apoptotic loss of CD4+ T cells has been proposed as a mechanism of T cell depletion in human immunodeficiency virus (HIV) infections resulting in immunodeficiency. The Env glycoprotein has been implicated in apoptosis of uninfected bystander cells via gp120 binding to CD4/CXC chemokine receptor 4 as well as the fusion/hemifusion process mediated by gp41. Using an in vitro model of coculture of Env-expressing cells as effectors and CD4+ T cells as targets, we find that apoptosis mediated by Env glycoprotein in bystander cells in fact correlates with gp41-induced hemifusion. Further, the apoptotic pathway initiated by this interaction involves caspase-3-dependent mitochondrial depolarization and reactive oxygen species production. HIV gp41-induced mitochondrial depolarization is inhibited by protease inhibitor nelfinavir but not by other HIV protease inhibitors or inhibitors of calpain and cathepsin. This "kiss of death" (hemifusion) signaling pathway is independent of p38 mitogen-activated protein kinase and p53, making it distinct from the apoptosis seen in syncytia. We also show that virion-induced apoptosis is gp41-dependent. Our findings provide new insights into the mechanism via which HIV gp41 mediates apoptosis in bystander cells.
authors.affiliation: NCI-Frederick, P.O. Box B, Building 469, Room 152, Miller Drive, Frederick, MD 21702-1201, USA.
authors.forename: Himanshu
authors.initials: H
authors.lastname: Garg
authors.forename: Robert
authors.initials: R
authors.lastname: Blumenthal
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D024201:Bystander Effect / Q000187:drug effects; D016466:CHO Cells; D053148:Caspase 3; D020169:Caspases / Q000276:immunology*; D018920:Coculture Techniques; D006224:Cricetinae; D015700:HIV Envelope Protein gp41 / Q000494:pharmacology*; D017320:HIV Protease Inhibitors / Q000494:pharmacology; D008561:Membrane Fusion / Q000276:immunology; D008928:Mitochondria / Q000187:drug effects* / Q000502:physiology; D019888:Nelfinavir / Q000494:pharmacology*; D017382:Reactive Oxygen Species / Q000276:immunology; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology
chemical_list: D015700:HIV Envelope Protein gp41; D017320:HIV Protease Inhibitors; D017382:Reactive Oxygen Species; C505407:CASP3 protein, human; D053148:Caspase 3; D020169:Caspases; D019888:Nelfinavir