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oai:repisalud.isciii.es:20.500.12105/166142025-06-09T08:53:24Zcom_20.500.12105_2052com_20.500.12105_2051com_20.500.12105_19604col_20.500.12105_19609col_20.500.12105_19605

00925njm 22002777a 4500 dc Lopez-Huertas, Maria Rosa author Mateos, Elena author Sanchez-Del Cojo, Maria author Gómez-Esquer, Francisco author Díaz-Gil, Gema author Rodríguez-Mora, Sara author Lopez, Juan Antonio author Calvo, Enrique author Lopez-Campos, Guillermo author Alcamí, José author Coiras, Mayte author 2013-03-15 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-κB-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-κB-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. J Biol Chem. 2013 Mar 15;288(11):7626-7644. 10.1074/jbc.M112.408294 1083-351X The Journal of biological chemistry 23364796 http://hdl.handle.net/20.500.12105/16614 The presence of HIV-1 Tat protein second exon delays fas protein-mediated apoptosis in CD4+ T lymphocytes: a potential mechanism for persistent viral production