Annibaldi Alessandro, Sajeva Angela, Muscolini Michela, Ciccosanti Fabiola, Corazzari Marco, Piacentini Mauro, Tuosto Loretta
Department of Cellular and Developmental Biology, Sapienza University of Rome, Rome, Italy.
Eur J Immunol. 2008 May;38(5):1446-51. doi: 10.1002/eji.200737854.
CD28 is one of the most important co-stimulatory receptors necessary for full T lymphocyte activation. CD28 can act as a TCR-independent signalling unit by delivering specific signals which may induce HIV transcription and replication. However, the mechanisms by which CD28 regulates HIV expression remain largely unknown. Here we show that the TCR-independent CD28 signals lead to the trans-activation of HIV-1 LTR in an NF-kappaB-dependent manner. In particular, we found that CD28 engagement by B7 induces the specific recruitment of RelA/NF-kappaB subunit to the HIV-1 LTR promoter both in vitro and in ex vivo infected cells. The results obtained by mutating specific tyrosine residues within the CD28 cytoplasmic tail as well as by using LY294002 inhibitory drug evidenced that the recruitment and activation of the phosphatidylinositol 3-kinase/Akt signalling pathway is crucial in mediating CD28-induced HIV transcription through RelA/NF-kappaB.
CD28是T淋巴细胞完全激活所必需的最重要的共刺激受体之一。CD28可通过传递特定信号充当独立于TCR的信号传导单位，这些信号可能诱导HIV转录和复制。然而，CD28调节HIV表达的机制在很大程度上仍不清楚。在此我们表明，独立于TCR的CD28信号以NF-κB依赖的方式导致HIV-1长末端重复序列（LTR）的反式激活。特别是，我们发现B7与CD28结合在体外和体内感染的细胞中均诱导RelA/NF-κB亚基特异性募集至HIV-1 LTR启动子。通过突变CD28胞质尾部的特定酪氨酸残基以及使用LY294002抑制药物所获得的结果证明，磷脂酰肌醇3激酶/蛋白激酶B（PI3K/Akt）信号通路的募集和激活在介导CD28通过RelA/NF-κB诱导的HIV转录中至关重要。
