CD4+ T cells from elite controllers resist HIV-1 infection by selective upregulation of p21
CD4+ T cells from elite controllers resist HIV-1 infection by selective upregulation of p21
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DOI：
10.1172/jci44539
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发表时间：
2011-04-01
影响因子：
15.9
通讯作者：
Lichterfeld, Mathias
中科院分区：
文献类型：
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作者：
Chen, Huabiao;Li, Chun;Lichterfeld, Mathias
精英控制者代表了一个独特的HIV-1感染者群体，在没有抗逆转录病毒治疗的情况下无法检测到HIV-1复制。然而，这些患者有效的病毒免疫防御机制仍不清楚。在这里，我们表明，与HIV-1进展者和HIV-1阴性者相比，精英控制者的CD 4（+）T细胞对HIV-1感染的敏感性较低。这种对HIV-1感染的部分抗性涉及前病毒DNA的较低有效的逆转录和mRNA转录，并与细胞周期蛋白依赖性激酶抑制剂p21（也称为cip-1和waf-1）的强烈和选择性上调有关。实验性阻断来自精英控制者的CD 4（+）T细胞中的p21导致病毒逆转录和mRNA产生的显著增加，并导致细胞周期蛋白依赖性激酶9（CDK 9）的更高酶活性，CDK 9作为HIV-1基因表达的转录共激活因子。这表明，p21通过抑制HIV-1有效复制所需的细胞周期蛋白依赖性激酶，在来自精英控制者的CD 4（+）T细胞中充当抗HIV-1感染的屏障。这些数据证明了精英控制者对HIV-1的宿主抗性机制，并可能为预防或治疗HIV-1感染的临床策略开辟新的前景。
Elite controllers represent a unique group of HIV-1-infected persons with undetectable HIV-1 replication in the absence of antiretroviral therapy. However, the mechanisms contributing to effective viral immune defense in these patients remain unclear. Here, we show that compared with HIV-1 progressors and HIV-1-negative persons, CD4(+) T cells from elite controllers are less susceptible to HIV-1 infection. This partial resistance to HIV-1 infection involved less effective reverse transcription and mRNA transcription from proviral DNA and was associated with strong and selective upregulation of the cyclin-dependent kinase inhibitor p21 (also known as cip-1 and waf-1). Experimental blockade of p21 in CD4(+) T cells from elite controllers resulted in a marked increase of viral reverse transcripts and mRNA production and led to higher enzymatic activities of cyclin-dependent kinase 9 (CDK9), which serves as a transcriptional coactivator of HIV-1 gene expression. This suggests that p21 acts as a barrier against HIV-1 infection in CD4(+) T cells from elite controllers by inhibiting a cyclin-dependent kinase required for effective HIV-1 replication. These data demonstrate a mechanism of host resistance to HIV-1 in elite controllers and may open novel perspectives for clinical strategies to prevent or treat HIV-1 infection.