Selliah Nithianandan, Zhang Mingce, White Sara, Zoltick Philip, Sawaya Bassel E, Finkel Terri H, Cron Randy Q
Division of Rheumatology, Department of Pediatrics, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
Virology. 2008 Nov 25;381(2):161-7. doi: 10.1016/j.virol.2008.08.033. Epub 2008 Oct 1.
FOXP3 is a necessary transcription factor for the development and function of CD4+ regulatory T-cells (Tregs). The role of Tregs in HIV-1 infection remains unclear. Here, we show that expression of FOXP3 in primary human CD4 T-cells significantly inhibits HIV-1 infection. Since FOXP3 inhibits NFAT activity, and NFAT proteins contribute to HIV-1 transcription, we explore a transcriptional repressive function of HIV-1 LTR by FOXP3. Over-expression of FOXP3 in primary CD4 T-cells inhibits wild-type HIV-1 LTR reporter activity, and truncation mutants demonstrate that repression of the LTR by FOXP3 requires the dual proximal NF kappaB/NFAT binding sites. Interestingly, FOXP3 decreases binding of NFAT2 to the HIV-1 LTR in vivo. Furthermore, FOXP3 does not inhibit infection of HIV-1 NL4-3 which is mutated to disrupt transcription factor binding at either proximal NFAT or NF kappaB binding sites. These data suggest that resistance of Tregs to HIV-1 infection is due to inhibition of HIV-1 LTR transcription by FOXP3.
FOXP3是CD4 +调节性T细胞（Tregs）发育和功能所必需的转录因子。Tregs在HIV-1感染中的作用仍不清楚。在此，我们表明原代人CD4 T细胞中FOXP3的表达显著抑制HIV-1感染。由于FOXP3抑制NFAT活性，且NFAT蛋白有助于HIV-1转录，我们探究了FOXP3对HIV-1 LTR的转录抑制功能。原代CD4 T细胞中FOXP3的过表达抑制野生型HIV-1 LTR报告基因活性，截短突变体表明FOXP3对LTR的抑制需要双近端NFκB/NFAT结合位点。有趣的是，FOXP3在体内降低NFAT2与HIV-1 LTR的结合。此外，FOXP3不抑制HIV-1 NL4-3的感染，HIV-1 NL4-3发生突变以破坏近端NFAT或NFκB结合位点处的转录因子结合。这些数据表明Tregs对HIV-1感染的抗性是由于FOXP3对HIV-1 LTR转录的抑制。
