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Tat-Induced FOXO3a Is a Key Mediator of Apoptosis in HIV-1-Infected Human CD4⁺ T Lymphocytes¹

Department of Medicine, Children’s Hospital Boston, and Department of Pediatrics, Harvard Medical School, Boston, MA 02115

The high mutation rate of HIV is linked to the generation of viruses expressing proteins with altered function whose impact on disease progression is unknown. We investigated how HIV-1 viruses lacking Env, Vpr, and Nef affect CD4⁺ T cell survival. We found that in the absence of these proteins, HIV-1-infected CD4⁺ primary T cells progress to the G₀ phase of the cell cycle and to cell death, indicating that viruses expressing inactive forms of these proteins can contribute to the CD4⁺ T cell decline as the wild-type virus, suggesting that other HIV proteins are responsible for inducing apoptosis. Apoptosis in these cells is triggered by the alteration of the Egr1-PTEN-Akt (early growth response-1/phosphate and tensin homolog deleted on chromosome 10/Akt) and p53 pathways, which converge on the FOXO3a (Forkhead box transcription factor O class 3a) transcriptional activator. The FOXO3a target genes Fas ligand and TRAIL, involved in the extrinsic apoptotic pathway, and PUMA, Noxa, and Bim, which are part of the intrinsic apoptotic pathway, were also up-regulated, indicating that HIV infection leads to apoptosis by the engagement of multiple apoptotic pathways. RNAi-mediated knockdown of Egr1 and FOXO3a resulted in reduced apoptosis in HIV-infected HeLa and CD4⁺ T cells, providing further evidence for their critical role in HIV-induced apoptosis and G₀ arrest. We tested the possibility that Tat is responsible for the T cell apoptosis observed with these mutant viruses. The induction of Egr1 and FOXO3a and its target genes was observed in Jurkat cells transduced by Tat alone. Tat-dependent activation of the Egr1-PTEN-FOXO3a pathway provides a mechanism for HIV-1-associated CD4⁺ T cell death.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This project was supported by National Institutes of Health Grant RO1 AI060398 (to A.A.).

² Address correspondence and reprint requests to Dr. Anna Aldovini, Children’s Hospital Boston, 300 Longwood Avenue, Boston, MA 02115. E-mail address: anna.aldovini{at}childrens.harvard.edu

³ Abbreviations used in this paper: FasL, Fas ligand; ATF3, human activating transcription factor 3; ATM, mutated in ataxia-telangiectasia; Bcl6, B cell lymphoma-6; eGFP, enhanced GFP; Egr1, early growth response protein-1; FOXO3a, Forkhead box transcription factor O class 3a; GADD45, growth arrest and DNA-damage-inducible; HSA, heat-stable Ag; MFI, mean fluorescence intensity; MOI, multiplicity of infection; ns, nonspecific; PTEN, phosphate and tensin homolog deleted on chromosome 10; rh, recombinant human; 7AAD, 7-aminoactinomycin D; siRNA, short interfering RNA; tTA, tet transactivator; VSV-G, vesicular stomatitis virus-G protein; PUMA, p53 up-regulated modulator of apoptosis.

⁴ The accession number for the DNA microarray data in GEO (Gene Expression Omnibus) is GSE12963.

⁵ The online version of this article contains supplemental material.