Journal
JOURNAL OF BIOLOGICAL CHEMISTRY
Volume 288, Issue 11, Pages 7626-7644Publisher
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M112.408294
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Funding
- Fundacion para la Investigacion y la Prevencion del Sida en Espana Grant [360924/10]
- Spanish Ministry of Economy and Competitiveness [SAF2010-18388]
- Spanish Ministry of Health [EC11-285]
- AIDS Network Instituto del Salud Carlos III-Redes Tematicas de Investigacion Cooperativa Grant [RD06/0006]
- Instituto de Salud Carlos III, Spanish Ministry of Economy and Competitiveness Grant Fondo de Investigaciones Sanitarias [PI080752]
- Network of Excellence EUROPRISE
- European Union
- Fondo de Investigaciones Sanitarias [FI09/00347]
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HIV-1 replication is efficiently controlled by the regulator protein Tat (101 amino acids) and codified by two exons, although the first exon (1-72 amino acids) is sufficient for this process. Tat can be released to the extracellular medium, acting as a soluble pro-apoptotic factor in neighboring cells. However, HIV-1-infected CD4(+) T lymphocytes show a higher resistance to apoptosis. We observed that the intracellular expression of Tat delayed FasL-mediated apoptosis in both peripheral blood lymphocytes and Jurkat cells, as it is an essential pathway to control T cell homeostasis during immune activation. Jurkat-Tat cells showed impairment in the activation of caspase-8, deficient release of mitochondrial cytochrome c, and delayed activation of both caspase-9 and -3. This protection was due to a profound deregulation of proteins that stabilized the mitochondrial membrane integrity, such as heat shock proteins, prohibitin, or nucleophosmin, as well as to the up-regulation of NF-kappa B-dependent anti-apoptotic proteins, such as BCL2, c-FLIPS, XIAP, and C-IAP2. These effects were observed in Jurkat expressing full-length Tat (Jurkat-Tat101) but not in Jurkat expressing the first exon of Tat (Jurkat-Tat72), proving that the second exon, and particularly the NF-kappa B-related motif ESKKKVE, was necessary for Tat-mediated protection against FasL apoptosis. Accordingly, the protection exerted by Tat was independent of its function as a regulator of both viral transcription and elongation. Moreover, these data proved that HIV-1 could have developed strategies to delay FasL-mediated apoptosis in infected CD4(+) T lymphocytes through the expression of Tat, thus favoring the persistent replication of HIV-1 in infected T cells.
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