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

María Rosa López-Huertas, Elena Mateos, María Sánchez Del Cojo, Francisco Gómez-Esquer, Gema Díaz-Gil, Sara Rodríguez-Mora, Juan Antonio López, Enrique Calvo, Guillermo López-Campos, José Alcamí, Mayte Coiras*

*Corresponding author for this work

Research output: Contribution to journalArticle

35 Citations (Scopus)

Abstract

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-κBdependent 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.

Original languageEnglish
Pages (from-to)7626-7644
Number of pages19
JournalJournal of Biological Chemistry
Volume288
Issue number11
DOIs
Publication statusPublished - 15 Mar 2013
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology

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  • Cite this

    López-Huertas, M. R., Mateos, E., Del Cojo, M. S., Gómez-Esquer, F., Díaz-Gil, G., Rodríguez-Mora, S., López, J. A., Calvo, E., López-Campos, G., Alcamí, J., & Coiras, M. (2013). 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. Journal of Biological Chemistry, 288(11), 7626-7644. https://doi.org/10.1074/jbc.M112.408294