Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
Virology. 2011 Dec 5;421(1):12-8. doi: 10.1016/j.virol.2011.09.002. Epub 2011 Oct 4.
We have previously reported that HIV-1 preferentially infects Foxp3+ Treg cells in vitro and in vivo, and Foxp3 enhances the HIV-1 LTR expression through epigenetic mechanisms in T cells. We report here that histone deacetylase inhibitor (HDACi) failed to further enhance HIV gene expression in FoxP3+ T cells. We discovered that Foxp3 inhibited cellular HDAC activity in T cells, and mutations in the forkhead domain that ablate Foxp3 function also abolished its ability to inhibit HDAC. When co-expressed, Foxp3 specifically inhibited the deacetylase activity of HDAC1. We further showed that Foxp3 was associated with HDAC1, and mutations in the forkhead domain that ablate Foxp3 function in Treg cells also inhibited Foxp3 association with and inhibition of HDAC1. Finally, Foxp3 failed to enhance HIV-1 gene expression in human T cells expressing HDAC1-specific shRNA. We conclude that Foxp3 modulates gene expression in human T cells at least partly by inhibiting HDAC1 activity.
我们之前曾报道过 HIV-1 在体外和体内优先感染 Foxp3+Treg 细胞，Foxp3 通过表观遗传机制增强 T 细胞中的 HIV-1LTR 表达。我们在这里报告称，组蛋白去乙酰化酶抑制剂（HDACi）未能进一步增强 Foxp3+T 细胞中的 HIV 基因表达。我们发现 Foxp3 抑制了 T 细胞中的细胞内 HDAC 活性，并且破坏 Foxp3 功能的叉头结构域中的突变也使其丧失了抑制 HDAC 的能力。当共表达时，Foxp3 特异性抑制了 HDAC1 的去乙酰化酶活性。我们进一步表明，Foxp3 与 HDAC1 相关，并且破坏 Treg 细胞中 Foxp3 功能的叉头结构域中的突变也抑制了 Foxp3 与和抑制 HDAC1 的关联。最后，Foxp3 未能增强表达 HDAC1 特异性 shRNA 的人 T 细胞中的 HIV-1 基因表达。我们得出结论，Foxp3 通过抑制 HDAC1 活性至少部分地调节人 T 细胞中的基因表达。
