title: Human immunodeficiency virus type 1 Tat protein inhibits the SIRT1 deacetylase and induces T cell hyperactivation.
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.
authors.affiliation: Gladstone Institute of Virology and Immunology, University of California, San Francisco, CA 94158, USA.
authors.forename: Hye-Sook
authors.initials: HS
authors.lastname: Kwon
authors.forename: Michael M
authors.initials: MM
authors.lastname: Brent
authors.forename: Ruth
authors.initials: R
authors.lastname: Getachew
authors.forename: Prerana
authors.initials: P
authors.lastname: Jayakumar
authors.forename: Lin-Feng
authors.initials: LF
authors.lastname: Chen
authors.forename: Martina
authors.initials: M
authors.lastname: Schnolzer
authors.forename: Michael W
authors.initials: MW
authors.lastname: McBurney
authors.forename: Ronen
authors.initials: R
authors.lastname: Marmorstein
authors.forename: Warner C
authors.initials: WC
authors.lastname: Greene
authors.forename: Melanie
authors.initials: M
authors.lastname: Ott
mesh_terms: D000818:Animals; D002460:Cell Line; D015497:HIV-1 / Q000276:immunology*; D006801:Humans; D008213:Lymphocyte Activation / Q000276:immunology*; D008239:Lysine / Q000378:metabolism; D051379:Mice; D011485:Protein Binding; D025941:Protein Interaction Mapping; D056564:Sirtuin 1; D037761:Sirtuins / Q000037:antagonists & inhibitors* / Q000172:deficiency / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology*; D051996:Transcription Factor RelA / Q000378:metabolism; D054322:tat Gene Products, Human Immunodeficiency Virus / Q000276:immunology* / Q000378:metabolism*
chemical_list: D051996:Transcription Factor RelA; D054322:tat Gene Products, Human Immunodeficiency Virus; C447939:SIRT1 protein, human; D056564:Sirtuin 1; D037761:Sirtuins; D008239:Lysine