艾滋病毒诱导造血抑制过程中的微 RNA 目标同源染色体信使 RNA

Prasad S. Koka, B. Ramdass
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引用次数: 0

摘要

细胞减少症是艾滋病毒/艾滋病患者和进展期患者因持续异常造血而导致的一种常见病。为了开发针对细胞减少症的有效疗法,有必要了解艾滋病病毒感染影响造血干祖细胞(HSPCs)分化、导致造血抑制并引发血液病的机制。目前,只有用于治疗艾滋病病毒感染的抗逆转录病毒药物,在间接降低病毒复制水平的同时,也能共同减轻细胞减少症。现有的证据表明,这种间接疗效可能不会在感染者的整个生命周期中持续存在,获得性免疫缺陷可能会超越病毒复制减少所带来的有益后果。正如本文所引述的,我们和我们的同事是首次涉足微小核糖核酸(microRNA)的研究,并将其作为治疗艾滋病病毒/艾滋病细胞减少症的潜在干预疗法。在这篇文章中,我们进一步研究了同源染色体基因调控导致细胞减少症的机制。此前,我们曾利用 SCID-hu Thy/Liv 动物实验证明,HIV-1 可抑制 CD34+ 细胞的多系造血。此外,我们还证明,尽管 CD34+ 细胞对 HIV-1 感染有抵抗力,但病毒诱导的造血抑制仍会发生。我们开始寻找 CD4+ T 细胞分泌的可能参与抑制耐 HIV 感染的 CD34+ 细胞造血的特定宿主因子。最近,我们报道了受病毒感染的 CD4+ 胸腺细胞分泌的 miRNA-15a 和 miRNA-24,它们在 HIV 感染后的不同表达间接抑制了造血。我们进而假设,在病毒感染的 T 细胞中观察到的 miRNA 差异表达会导致 CD34+ 细胞中同种异体(HOX)基因编码转录组的异常调控,影响特定的 MAPK 信号传导和 CD34+ 细胞的命运,从而破坏正常的造血功能。我们发现,在艾滋病病毒感染中,miRNA 介导的 HOXB3 mRNA 转录后失调抑制了多系造血,从而导致病毒感染的艾滋病患者出现血液病。这些观察结果预示着特定的 microRNA 候选物对病毒引起的细胞减少症具有潜在疗效,否则现有的 HAART/ART 方案无法治疗这些细胞减少症。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
MicroRNA target homeobox messenger RNA in HIV induced hematopoietic inhibition
Cytopenias are a common occurrence due to abnormal hematopoiesis persistent in patients suffering from and advancing with HIV/AIDS. In order to develop efficacious therapies against cytopenias, it is necessary to understand the mechanisms by which HIV infection affects the differentiation of hematopoietic stem-progenitor cells (HSPCs), causing hematopoietic inhibition, that leads to hematological disorders. Currently, only the antiretrovirals that are being used to treat HIV infection and indirectly lower the levels of virus replication also co-attenuate cytopenias. The evidence available suggests that this indirect efficacy may not prevail for the lifetime of the infected patients, and the acquired immunodeficiency can overtake the beneficial consequences of decreased virus replication. As cited in this article, we and our colleagues are the first to make a foray into the involvement of microRNAs and their use as potential interventional treatments for the cytopenias that occur with HIV/AIDS. Herein, we progressed further in the direction of the mechanisms of the involvement of homeobox gene regulation to cause cytopenias. We had previously shown that HIV-1 inhibits multi-lineage hematopoiesis of the CD34+ cells using SCID-hu Thy/Liv animals in vivo. Furthermore, we demonstrated that the virus-induced hematopoietic inhibition occurred despite the CD34+ cells being resistant to HIV-1 infection. We set out to search for the specific host factors secreted by CD4+ T-cells that likely participate in the inhibition of hematopoiesis of the HIV infection-resistant CD34+ cells. More recently, we reported the identification of virus-infected CD4+ thymocyte-secreted miRNA-15a and miRNA-24 and that their differential expression following HIV infection causes the indirect inhibition of hematopoiesis. We then hypothesized that the observed miRNA differential expression in the virus-infected T-cells causes the abnormal regulation of homeobox (HOX) gene-encoded transcriptomes in the CD34+ cells, affecting specific MAPK signaling and CD34+ cell fate, thereby disrupting normal hematopoiesis. We present that in HIV infection, miRNA-mediated post-transcriptional dysregulation of HOXB3 mRNA inhibits multi-lineage hematopoiesis, which translates into hematological disorders in virus-infected patients with HIV/AIDS. These observations portend specific microRNA candidates for potential efficacy against the virus-induced cytopenias that are otherwise not treatable by the existing HAART/ART regimens, which are primarily designed and applicable for the attenuation of virus replication.
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