Kwon Hye-Sook, Brent Michael M, Getachew Ruth, Jayakumar Prerana, Chen Lin-Feng, Schnolzer Martina, McBurney Michael W, Marmorstein Ronen, Greene Warner C, Ott Melanie
Gladstone Institute of Virology and Immunology, University of California, San Francisco, CA 94158, USA.
Cell Host Microbe. 2008 Mar 13;3(3):158-67. doi: 10.1016/j.chom.2008.02.002.
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.
T细胞过度激活的症状决定了HIV-1感染的进程和结果，但这种慢性免疫激活背后的机制尚未完全明确。我们发现病毒反式激活因子Tat通过阻断烟酰胺腺嘌呤二核苷酸（NAD(+)）依赖性去乙酰化酶SIRT1来促进T细胞过度激活。Tat直接与SIRT1的去乙酰化酶结构域相互作用，并阻断SIRT1使NF-κB的p65亚基中赖氨酸310去乙酰化的能力。由于乙酰化的p65作为转录因子更具活性，Tat使NF-κB反应性基因的表达过度激活，而这一功能在SIRT1基因敲除细胞中丧失。这些结果支持了一种模型，即在HIV感染期间，Tat抑制了SIRT1作为T细胞激活负调节因子的正常功能。这些事件可能导致了在HIV感染个体中发现的免疫细胞过度激活状态。
