Lopez-Huertas, Maria RosaMateos, ElenaSanchez-Del Cojo, MariaGómez-Esquer, FranciscoDíaz-Gil, GemaRodriguez‑Mora, SaraLopez, Juan AntonioCalvo, EnriqueLopez-Campos, GuillermoAlcamí, JoséCoiras, Mayte2018-11-302018-11-302013-03-15J Biol Chem. 2013; 288(11):7626-440021-9258http://hdl.handle.net/20.500.12105/6749Versión definitiva disponible en: http://hdl.handle.net/20.500.12105/16614HIV-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.engSMURhttps://creativecommons.org/licenses/by/4.0/CD4-Positive T-LymphocytesCaspase 3Caspase 8Caspase 9Cytochromes cExonsHIV-1HumansJurkat CellsMitochondriaMutagenesis, Site-DirectedNF-kappa BOligonucleotide Array Sequence AnalysisProteomeProteomicsTransfectionFas Receptortat Gene ProductsApoptosisGene Expression RegulationHuman Immunodeficiency VirusAttribution 4.0 International23364796288117626-4410.1074/jbc.M112.408294The Journal of biological chemistryopen access