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

• Published in: The Journal of biological chemistry Vol. 288; no. 11; pp. 7626 - 7644
• Main Authors: López-Huertas, María Rosa, Mateos, Elena, Sánchez Del Cojo, María, Gómez-Esquer, Francisco, Díaz-Gil, Gema, Rodríguez-Mora, Sara, López, Juan Antonio, Calvo, Enrique, López-Campos, Guillermo, Alcamí, José, Coiras, Mayte
• Format: Journal Article
• Language: English
• Published: United States American Society for Biochemistry and Molecular Biology 15.03.2013
• Subjects: Apoptosis; Caspase 3 - metabolism; Caspase 8 - metabolism; Caspase 9 - metabolism; CD4-Positive T-Lymphocytes - metabolism; CD4-Positive T-Lymphocytes - virology; Cytochromes c - metabolism; Exons; fas Receptor - metabolism; Gene Expression Regulation; HIV-1 - metabolism; Humans; Jurkat Cells; Mitochondria - metabolism; Molecular Bases of Disease; Mutagenesis, Site-Directed; NF-kappa B - metabolism; Oligonucleotide Array Sequence Analysis; Proteome; Proteomics - methods; tat Gene Products, Human Immunodeficiency Virus - metabolism; Transfection
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M112.408294

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.