Laboratory of Human Retrovirology, Institut de Recherches Cliniques de Montréal, Montreal, QC H2W 1R7, Canada.
Department of Microbiology, Infectious Diseases and Immunology, Faculty of Medicine, Université de Montréal, Montreal, QC H3C 3J7, Canada.
Viruses. 2024 Jul 4;16(7):1076. doi: 10.3390/v16071076.
MicroRNAs (miRNAs) play important roles in the control of HIV-1 infection. Here, we performed RNA-seq profiling of miRNAs and mRNAs expressed in CD4 T lymphocytes upon HIV-1 infection. Our results reveal significant alterations in miRNA and mRNA expression profiles in infected relative to uninfected cells. One of the miRNAs markedly downregulated in infected cells is miRNA-26a. Among the putative targets of miRNA-26a are CD59 receptor transcripts, which are significantly upregulated in infected CD4 T cells. The addition of miRNA-26a mimics to CD4 T cells reduces CD59 at both the mRNA and surface protein levels, validating CD59 as a miRNA-26a target. Consistent with the reported inhibitory role of CD59 in complement-mediated lysis (CML), knocking out CD59 in CD4 T cells renders both HIV-1-infected cells and progeny virions more prone to antibody-dependent CML (ADCML). The addition of miRNA-26a mimics to infected cells leads to enhanced sensitivity of progeny virions to ADCML, a condition linked to a reduction in CD59 packaging into released virions. Lastly, HIV-1-mediated downregulation of miRNA-26a expression is shown to be dependent on integrated HIV-1 expression but does not involve viral accessory proteins. Overall, these results highlight a novel mechanism by which HIV-1 limits ADCML by upregulating CD59 expression via miRNA-26a downmodulation.
微小 RNA（miRNAs）在 HIV-1 感染的控制中发挥着重要作用。在这里，我们对 HIV-1 感染后 CD4 T 淋巴细胞中表达的 miRNAs 和 mRNAs 进行了 RNA-seq 谱分析。我们的结果揭示了感染细胞与未感染细胞相比，miRNA 和 mRNA 表达谱发生了显著变化。在感染细胞中明显下调的 miRNA 之一是 miRNA-26a。miRNA-26a 的潜在靶标之一是 CD59 受体转录本，其在感染的 CD4 T 细胞中显著上调。将 miRNA-26a 模拟物添加到 CD4 T 细胞中，可降低 CD59 在 mRNA 和表面蛋白水平上的表达，验证了 CD59 是 miRNA-26a 的靶标。与 CD59 在补体介导的溶解（CML）中抑制作用的报道一致，敲除 CD4 T 细胞中的 CD59 会使 HIV-1 感染的细胞和子代病毒颗粒更容易受到抗体依赖性 CML（ADCML）的影响。将 miRNA-26a 模拟物添加到感染的细胞中，会导致子代病毒颗粒对 ADCML 的敏感性增强，这种情况与 CD59 包装到释放的病毒颗粒中的减少有关。最后，研究表明，HIV-1 介导的 miRNA-26a 表达下调依赖于整合的 HIV-1 表达，但不涉及病毒辅助蛋白。总的来说，这些结果强调了一种新的机制，即 HIV-1 通过下调 miRNA-26a 表达来上调 CD59 表达，从而限制 ADCML。
