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Tat-induced FOXO3a is a key mediator of apoptosis in HIV-1-infected human CD4+ T lymphocytes.

ABSTRACT: 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 G(0) 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 G(0) 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.

SUBMITTER: Dabrowska A

PROVIDER: S-EPMC2665797 | biostudies-literature | 2008 Dec

REPOSITORIES: biostudies-literature

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Tat-induced FOXO3a is a key mediator of apoptosis in HIV-1-infected human CD4+ T lymphocytes.

Dabrowska Alicja A Kim Nayoung N Aldovini Anna A

Journal of immunology (Baltimore, Md. : 1950) 20081201 12

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 G(0) phase of the cell cycle and to cell death, indicating that viruses expressing inactive forms of these proteins can contribute to the CD4(+) T c ...[more]

PMID: 19050264

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Project description:Human immunodeficiency virus type 1 (HIV-1) infection is characterized by progressive depletion of CD4+ T lymphocytes and dysfunction of the immune system. The numbers of CD4+ T lymphocytes in the human body are maintained constantly by homeostatic mechanisms that failed during HIV-1 infection, resulting in progressive loss of CD4+ T cells mainly via apoptosis. Recently, a non-apoptotic form of necrotic programmed cell death, named necroptosis, has been investigated in many biological and pathological processes. We then determine whether HIV-1-infected cells also undergo necroptosis. In this report, we demonstrate that HIV-1 not only induces apoptosis, but also mediates necroptosis in the infected primary CD4+ T lymphocytes and CD4+ T-cell lines. Necroptosis-dependent cytopathic effects are significantly increased in HIV-1-infected Jurkat cells that is lack of Fas-associated protein-containing death domain (FADD), indicating that necroptosis occurs as an alternative cell death mechanism in the absence of apoptosis. Unlike apoptosis, necroptosis mainly occurs in HIV-infected cells and spares bystander damage. Treatment with necrostatin-1(Nec-1), a RIP1 inhibitor that specifically blocks the necroptosis pathway, potently restrains HIV-1-induced cytopathic effect and interestingly, inhibits the formation of HIV-induced syncytia in CD4+ T-cell lines. This suggests that syncytia formation is mediated, at least partially, by necroptosis-related processes. Furthermore, we also found that the HIV-1 infection-augmented tumor necrosis factor-alpha (TNF-α) plays a key role in inducing necroptosis and HIV-1 Envelope and Tat proteins function as its co-factors. Taken together,necroptosis can function as an alternative cell death pathway in lieu of apoptosis during HIV-1 infection, thereby also contributing to HIV-1-induced cytopathic effects. Our results reveal that in addition to apoptosis, necroptosis also plays an important role in HIV-1-induced pathogenesis.

Dataset Information

Tat-induced FOXO3a is a key mediator of apoptosis in HIV-1-infected human CD4+ T lymphocytes.

Publications

Tat-induced FOXO3a is a key mediator of apoptosis in HIV-1-infected human CD4+ T lymphocytes.

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