Human Immunodeficiency Virus Type 1 Tat Protein Inhibits the SIRT1 Deacetylase and Induces T Cell Hyperactivation

Gladstone Institute of Virology and Immunology, University of California, San Francisco, CA 94158, USA.
Cell host & microbe (Impact Factor: 12.19). 04/2008; 3(3):158-67. DOI: 10.1016/j.chom.2008.02.002
Source: PubMed

ABSTRACT Symptoms of T cell hyperactivation shape the course and outcome of HIV-1 infection, but the mechanism(s) underlying this chronic immune activation are not well understood. We find that the viral transactivator Tat promotes hyperactivation of T cells by blocking the nicotinamide adenine dinucleotide (NAD(+))-dependent deacetylase SIRT1. Tat directly interacts with the deacetylase domain of SIRT1 and blocks the ability of SIRT1 to deacetylate lysine 310 in the p65 subunit of NF-kappaB. Because acetylated p65 is more active as a transcription factor, Tat hyperactivates the expression of NF-kappaB-responsive genes, a function lost in SIRT1-/- cells. These results support a model where the normal function of SIRT1 as a negative regulator of T cell activation is suppressed by Tat during HIV infection. These events likely contribute to the state of immune cell hyperactivation found in HIV-infected individuals.

    • "Studies reveal that SIRT1 exerts effects on the immune system by regulating the activity of T cells. Kwon et al. (2008) reported that blocking SIRT1 induces T cell hyperactivation, suggesting that SIRT1 acts as a negative regulator of T cell activation. Zhang et al. (2009) also found that the loss of SIRT1 functionality resulted in abnormally increased T cell activation and a breakdown of CD4þ T cell tolerance and that conversely, the upregulation of SIRT1 expression led to T cell anergy. "
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    • "The acetylation of the RelA subunit of NF-kB by p300 increases its transcriptional activity (Chen et al., 2002) and this is countered by the cellular deacetylase SIRT1 (Yeung et al., 2004). SIRT1 activity is in turn blocked by HIV-1 Tat (Kwon et al., 2008). In addition, it has been demonstrated that HIV Tat and Rev transcripts are retained in the nuclei of resting CD4 + T-cells (Lassen et al., 2006) and that numerous host microRNAs can directly or indirectly downregulate HIV-1 gene expression, contributing to the maintenance of proviral latency (Chiang & Rice, 2012). "
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    • "Of note, SIRT1-mediated deacetylation of RelA at lysine 310 is blocked by HIV Tat. Because acetylation of lysine 310 in RelA greatly enhances transcriptional activity, this inhibitory effect of Tat could markedly boost NF-kB action and increase viral gene expression as well as expression of genes involved in inflammation and immune activation (Kwon et al. 2008). Importantly, HDAC3-mediated deacetylation of lysine 221 restores the ability of newly synthesized IkBa to bind to RelA (Sun et al. 1993), "
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