Background Some multifunctional cellular proteins, as the monocyte chemotactic protein-induced protein 1 (ZC3H12A/MCPIP1) and the cyclin-dependent kinase inhibitor CDKN1A/p21, are able to modulate the cellular susceptibility to the human immunodeficiency virus type 1 (HIV-1). Several studies showed that CDKN1A/p21 is expressed at high levels ex vivo in cells from individuals who naturally control HIV-1 replication (HIC) and a recent study supports a coordinate regulation of ZC3H12A/MCPIP1 and CDKN1A/p21 transcripts in a model of renal carcinoma cells. Here, we explored the potential associations between mRNA expression of ZC3H12A/MCPIP1 and CDKN1A/p21 in HIC sustaining undetectable (elite controllers–EC) or low (viremic controllers–VC) viral loads. Results We found a selective upregulation of ZC3H12A/MCPIP1 and CDKN1A/p21 mRNA levels in PBMC from HIC compared with both ART–suppressed and HIV–negative control groups (P≤ 0.02) and higher MCPIP1 and p21 proteins levels in HIC than in HIV-1 negative subjects. There was a moderate positive correlation (r ≥ 0.57; P ≤ 0.014) between expressions of both transcripts in HIC and in HIC combined with control groups. We found positive correlations between the mRNA level of CDKN1A/p21 with activated CD4 + T cells levels in HIC (r ≥ 0.53; P ≤ 0.017) and between the mRNA levels of both CDKN1A/p21 (r = 0.74; P = 0.005) and ZC3H12A/MCPIP1 (r = 0.58; P = 0.040) with plasmatic levels of sCD14 in EC. Reanalysis of published transcriptomic data confirmed the positive association between ZC3H12A/MCPIP1 and CDKN1A/p21 mRNA levels in CD4 + T cells and monocytes from disparate cohorts of HIC and other HIV-positive control groups. Conclusions These data show for the first time the simultaneous upregulation of ZC3H12A/MCPIP1 and CDKN1A/p21 transcripts in the setting of natural suppression of HIV-1 replication in vivo and the positive correlation of the expression of these cellular factors in disparate cohorts of HIV-positive individuals. The existence of a common regulatory pathway connecting ZC3H12A/MCPIP1 and CDKN1A/p21 could have a synergistic effect on HIV-1 replication control and pharmacological manipulation of these multifunctional host factors may open novel therapeutic perspectives to prevent HIV-1 replication and disease progression.

中文翻译：

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HIV-1 控制者中 CDKN1A/p21 的表达增加与 ZC3H12A/MCPIP1 的上调相关

背景 一些多功能细胞蛋白，如单核细胞趋化蛋白诱导蛋白 1 (ZC3H12A/MCPIP1) 和细胞周期蛋白依赖性激酶抑制剂 CDKN1A/p21，能够调节细胞对 1 型人类免疫缺陷病毒 (HIV-1) 的易感性. 几项研究表明 CDKN1A/p21 在来自自然控制 HIV-1 复制 (HIC) 的个体的细胞中体外高水平表达，最近的一项研究支持 ZC3H12A/MCPIP1 和 CDKN1A/p21 转录物在肾脏模型中的协调调节癌细胞。在这里，我们探讨了 HIC 中 ZC3H12A/MCPIP1 和 CDKN1A/p21 的 mRNA 表达之间的潜在关联，这些 HIC 维持无法检测到（精英控制者-EC）或低（病毒控制者-VC）病毒载量。结果我们发现与 ART 抑制组和 HIV 阴性对照组（P≤0.02）相比，HIC PBMC 中 ZC3H12A/MCPIP1 和 CDKN1A/p21 mRNA 水平选择性上调，并且 HIC 中的 MCPIP1 和 p21 蛋白水平高于 HIV- 1 消极科目。在 HIC 和 HIC 与对照组结合的两种转录本的表达之间存在中度正相关（r ≥ 0.57；P ≤ 0.014）。我们发现 CDKN1A/p21 的 mRNA 水平与 HIC 中活化的 CD4 + T 细胞水平之间呈正相关（r ≥ 0.53；P ≤ 0.017）以及 CDKN1A/p21 的 mRNA 水平（r = 0.74；P = 0.005）和ZC3H12A/MCPIP1 (r = 0.58; P = 0.040) 与 EC 中 sCD14 的血浆水平。对已发表的转录组学数据的重新分析证实了来自不同 HIC 和其他 HIV 阳性对照组的 CD4 + T 细胞和单核细胞中 ZC3H12A/MCPIP1 和 CDKN1A/p21 mRNA 水平之间的正相关。结论 这些数据首次表明，在体内 HIV-1 复制自然抑制的情况下，ZC3H12A/MCPIP1 和 CDKN1A/p21 转录本的同时上调，以及这些细胞因子在不同的 HIV-积极的个人。连接 ZC3H12A/MCPIP1 和 CDKN1A/p21 的共同调控通路的存在可能对 HIV-1 复制控制和这些多功能宿主因子的药理学操作产生协同作用，可能为防止 HIV-1 复制和疾病进展开辟新的治疗前景。