Extracellular Nef Protein Targets CD4 + T Cells for Apoptosis by Interacting with CXCR4 Surface Receptors

Author:

James Cleve O.1,Huang Ming-Bo1,Khan Mafuz1,Garcia-Barrio Minerva2,Powell Michael D.1,Bond Vincent C.1

Affiliation:

1. Department of Microbiology/Immunology/Biochemistry

2. Cardiovascular Research Institute, Morehouse School of Medicine, Atlanta, Georgia

Abstract

ABSTRACT The effects of soluble Nef protein on CD4 + T cells were examined. CD4 + -T-cell cultures exposed to soluble Nef were analyzed for apoptosis by terminal deoxynucleotidyltransferase-mediated dUTP-biotin nick end labeling and hallmarks of apoptosis including cytoplasmic shrinkage, nuclear fragmentation, DNA laddering, and caspase activation. We observed dose- and time-dependent inductions of apoptosis. DNA laddering and activated caspase 3 were also evident. Cells treated with Nef/protein kinase inhibitor complexes were protected from Nef-induced apoptosis, suggesting possible roles for protein kinases in the apoptosis pathway. Similarly, cells treated with Nef/anti-Nef antibody complexes were protected from Nef-induced apoptosis. The cellular receptor responsible for Nef-induced apoptosis was identified through antibody- and ligand-blocking experiments as a receptor commonly involved in viral entry. CXCR4 antibodies, as well as the endogenous ligand SDF-1α, were effective in blocking Nef-induced apoptosis, while CCR5 and CD4 antibodies were ineffective. Moreover, a CXCR4-deficient cell line, MDA-MB-468, which was resistant to Nef-induced apoptosis, became sensitive upon transfection with a CXCR4-expressing vector. This study suggests that extracellular Nef protein could contribute to the decline of CD4 counts prior to and during the onset of AIDS in patients with human immunodeficiency virus type 1 infections.

Publisher

American Society for Microbiology

Subject

Virology,Insect Science,Immunology,Microbiology

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