Human immunodeficiency virus type 1 Tat protein inhibits the SIRT1 deacetylase and induces T cell hyperactivation.
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.
Kwon
Hye-Sook
HS
Gladstone Institute of Virology and Immunology, University of California, San Francisco, CA 94158, USA.
Brent
Michael M
MM
Getachew
Ruth
R
Jayakumar
Prerana
P
Chen
Lin-Feng
LF
Schnolzer
Martina
M
McBurney
Michael W
MW
Marmorstein
Ronen
R
Greene
Warner C
WC
Ott
Melanie
M
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*
D051996:Transcription Factor RelA; D054322:tat Gene Products, Human Immunodeficiency Virus; C447939:SIRT1 protein, human; D056564:Sirtuin 1; D037761:Sirtuins; D008239:Lysine