Association of Tat with Promoters of PTEN and PP2A Subunits Is Key to Transcriptional Activation of Apoptotic Pathways in HIV-Infected CD4+ T Cells

Abstract

Apoptosis in HIV-1-infected CD4+ primary T cells is triggered by the alteration of the PI3K and p53 pathways, which converge on the FOXO3a transcriptional activator. Tat alone can cause activation of FOXO3a and of its proapoptotic target genes. To understand how Tat affects this pathway, we carried out ChIP-Chip experiments with Tat. Tat associates with the promoters of PTEN and two PP2A subunit genes, but not with the FOXO3a promoter. PTEN and PP2A encode phosphatases, whose levels and activity are increased when Tat is expressed. They counteract phosphorylation of Akt1 and FOXO3a, and so activate transcriptional activity of FOXO3a. FOXO3a promotes increased transcription of Egr-1, which can further stimulate the transcription of PTEN, thereby reinforcing the pathway that leads to FOXO3a transcriptional activation. RNAi experiments support the role of PTEN and PP2A in the initiation of the Tat-mediated cascade, which is critical to apoptosis. The increased accumulation of PTEN and PP2A subunit mRNAs during Tat expression is more likely to be the result of increased transcription initiation and not relief of promoter-proximal pausing of RNAPII. The Tat-PTEN and -PP2A promoter interactions provide a mechanistic explanation of Tat-mediated apoptosis in CD4+ T cells.

Clionosterol and Ethyl Cholestan-22-enol Isolated from the Rhizome of <i>Polygala tenuifolia</i> Inhibit Phosphatidylinositol 3-Kinase/Akt Pathway

“…1,6,8) HIV-1 also indirectly hijacks this pathway in macrophages by inhibiting the negative regulator of the pathway, PTEN, which expands the life span of the infected macrophages exposed to various virus-induced toxic stresses and contributes to the establishment of the long-living viral reservoirs. 5,8) Inhibition of the PI3K/Akt cell survival pathway is high attractive anti-cancer and anti-HIV-1 therapies.…”

“…Of them, the expression of Tat appears to inactivate a negative regulator of the PI3K/Akt pathway, called PTEN. 5,6) The PI3K/Akt pathway is also highly activated in many cancer cell types. 7) For example, the transfection of HIV-1 Tat into CHME5 cells, a human microglial cell line, and human primary macrophages elevates their cytoprotective phenotypes against cellular stresses.…”

“…7) For example, the transfection of HIV-1 Tat into CHME5 cells, a human microglial cell line, and human primary macrophages elevates their cytoprotective phenotypes against cellular stresses. 6,8) More specifically, the Tat-expressing CHME5 cells activate the PI3K/Akt pathway upon exposure to cellular stresses by reducing the level of PTEN. 5,8) These cells render strong resistance to extracellular stresses such as lipopolysaccharide (LPS) or nitric oxide.…”

Poligapolide, a PI3K/Akt Inhibitor in Immunodeficiency Virus Type 1 TAT-Transduced CHME5 Cells, Isolated from the Rhizome of <i>Polygala tenuifolia</i>

“…Of them, HIV-1 Tat appears to inactivate phosphatase and tensin homology (PTEN), a negative regulator of the PI3K/Akt pathway. 3,4) For example, the transfection of HIV-1 Tat into CHME5 cells, a human microglial cell line, and human primary macrophages elevates their cytoprotective phenotypes against cellular stresses. 4,5) More specifically, the HIV-1 Tat-expressing CHME5 cells activate the PI3K/Akt pathway upon exposure to cellular stresses by reducing the level of PTEN.…”

“…3,4) For example, the transfection of HIV-1 Tat into CHME5 cells, a human microglial cell line, and human primary macrophages elevates their cytoprotective phenotypes against cellular stresses. 4,5) More specifically, the HIV-1 Tat-expressing CHME5 cells activate the PI3K/Akt pathway upon exposure to cellular stresses by reducing the level of PTEN. 3,5) These cells render strong resistance to extracellular stresses such as lipopolysaccharide (LPS) or nitric oxide.…”