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A more recent version of this article appeared on February 1, 2006

Published online before print December 5, 2005
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© by The Society for Leukocyte Biology
Journal of Leukocyte Biology, doi:10.1189/jlb.0805430

Received for publication August 2, 2005.
Revised October 7, 2005.
Accepted for publication October 17, 2005.

Article

HIV gp41-induced apoptosis is mediated by caspase-3-dependent mitochondrial depolarization, which is inhibited by HIV protease inhibitor nelfinavir

Himanshu Garg and Robert Blumenthal @

Center for Cancer Research Nanobiology Program, National Cancer Institute, National Institutes of Health, Frederick, Maryland

@ To whom correspondence should be addressed. E-mail: blumen{at}helix.nih.gov.


  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.

Key Words: hemifusion • Env glycoprotein • CXCR4




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