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
Reference68 articles.
1. Akari, H., Y. Yamamoto, H. Hiwada, Y. Saito, N. Takayanagi, A. H. Koyama, and A. Adachi. 1998. Suppression of HIV-1 replication in peripheral blood mononuclear cells by fasudil. J. Med. Investig.44:211-214.
2. Albini, A., S. Ferrini, R. Benelli, S. Sforzini, D. Giunciuglio, M. G. Aluigi, A. E. Proudfoot, S. Alouani, T. N. Wells, G. Mariani, R. L. Rabin, J. M. Farber, and D. M. Noonan. 1998. HIV-1 Tat protein mimicry of chemokines. Proc. Natl. Acad. Sci. USA95:13153-13158.
3. Anderson, R. W., M. S. Ascher, and H. W. Sheppard. 1998. Direct HIV cytopathicity cannot account for CD4 decline in AIDS in the presence of homeostasis: a worst-case dynamic analysis. J. Acquir. Immune Defic. Syndr. Hum. Retrovirol.17:245-252.
4. Arold, S., F. Hoh, S. Domergue, C. Birck, M. A. Delsuc, M. Jullien, and C. Dumas. 2000. Characterization and molecular basis of the oligomeric structure of HIV-1 nef protein. Protein Sci.9:1137-1148.
5. Azad, A. A. 2000. Could Nef and Vpr proteins contribute to disease progression by promoting depletion of bystander cells and prolonged survival of HIV-infected cells? Biochem. Biophys. Res. Commun.267:677-685.
Cited by
104 articles.
订阅此论文施引文献
订阅此论文施引文献,注册后可以免费订阅5篇论文的施引文献,订阅后可以查看论文全部施引文献