Production of specific mRNA transcripts, usage of an alternate promoter, and octamer-binding transcription factors influence the surface expression levels of the HIV cereceptor CCR5 on primary T cells
Production of specific mRNA transcripts, usage of an alternate promoter, and octamer-binding transcription factors influence the surface expression levels of the HIV cereceptor CCR5 on primary T cells
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DOI：
10.4049/jimmunol.178.9.5668
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发表时间：
2007-05-01
影响因子：
4.4
通讯作者：
Ahnja, Sunil K.
中科院分区：
文献类型：
--
作者：
Mummidi, Srinivas;Adams, Lisa M.;Ahnja, Sunil K.
记忆性CD 4 + T细胞表面CCR 5水平影响HIV-1/AIDS易感性替代启动子的使用导致CCR 5 mRNA同种型的产生，所述同种型基于它们是否含有或缺乏非翻译外显子1而不同。含外显子1的转录物对CCR 5表面表达的影响尚不清楚。在这项研究中，我们表明，增加细胞表面表达的CCR 5对原代T细胞与选择性富集外显子1的转录本。驱动含外显子I的转录物的启动子在原代人T细胞中高度活跃，但在转化的T细胞系中不活跃。转录因子Oct-1和Oct-2分别抑制和增强含外显子1的转录物的表达和CCR 5表面水平。然而，在同源八聚体结合位点的多态性在非人灵长类动物的CCR 5启动子废除这些转录因子的结合。这些结果确定外显子1的转录本，和顺-反的因素，调节这些mRNA亚型的表达水平的关键参数，影响CCR 5表面表达水平，并通过扩展，人类之间的艾滋病毒/艾滋病的易感性，并可能，观察到的物种间差异，慢病毒感染的易感性。免疫学杂志，2007，178：5668-.5681.
Surface levels of CCR5 on memory CD4+ T cells influence HIV-1/AIDS susceptibility. Alternative promoter usage results in the generation of CCR5 mRNA isoforms that differ based on whether they contain or lack the untranslated exon 1. The impact of exon 1-containing transcripts on CCR5 surface expression is unknown. In this study, we show that the increased cell surface expression of CCR5 on primary T cells is associated with selective enrichment of exon 1-containing transcripts. The promoter that drives exon I-containing transcripts is highly active in primary human T cells but not in transformed T cell lines. The transcription factors Oct-1 and -2 inhibit and enhance, respectively, the expression of exon 1-containing transcripts and CCR5 surface levels. However, polymorphisms at homologous octamer-binding sites in the CCR5 promoter of nonhuman primates abrogate the binding of these transcription factors. These results identify exon 1-containing transcripts, and the cis-trans factors that regulate the expression levels of these mRNA isoforms as key parameters that affect CCR5 surface expression levels, and by extension, susceptibility to HIV/AIDS among humans, and possibly, the observed interspecies differences in susceptibility to lentiviral infection. The Journal of Immunology, 2007, 178: 5668-.5681.