The lab’s interest in this area started when we showed in 1996 that Tat hyperactivates HIV-infected T cells by amplifying signals through the CD28 coreceptor and NF-kappa B transcription factors. We later showed that Tat inhibits the NAD+-dependent deacetylase SIRT1 leading to hyperacetylation and hyperactivation of NF-kappa B. We have since further explored the immune regulatory role of SIRT1 and showed that it plays a critical role in the balance between immune suppressive regulatory T cells (Tregs) and pro-inflammatory Th17 cells by directly deacetylating the FoxP3 and RoR-gamma-t transcription factors. The control of Treg and Th17 responses is a key determinant of immune self-tolerance, and thus represents a vital front in the search for new therapies against autoimmunity. We are currently exploring the efficacy of SIRT1-modulating compounds in the treatment of autoimmune diseases such as Type 1 Diabetes and look for other epigenetic modifiers critical in this context. In addition, we are linking the known metabolic functions of SIRT1 with T cell biology to develop a new concept of immune aging in HIV disease and beyond.
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Kwon H-S, Brent MM, Getachew R, Jayakumar P, Chen L-F, Schnolzer M, McBurney MW, Marmorstein R, Greene WC, Ott M (2008) Human immunodeficiency virus type 1 Tat protein inhibits the SIRT1 deacetylase and induces T cell hyperactivation. Cell Host Microbe 3:158–167
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