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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Erythromycin derivatives inhibit HIV-1 replication in macrophages through modulation of MAPK activity to induce small isoforms of C/EBPβ
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Erythromycin derivatives inhibit HIV-1 replication in macrophages through modulation of MAPK activity to induce small isoforms of C/EBPβ

机译：红霉素衍生物通过调节MAPK活性来诱导C /EBPβ的小亚型，从而抑制巨噬细胞中的HIV-1复制。

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Macrophages (MΦs) are a major source of HIV-1 especially in patients with tuberculosis. There are MΦs that are permissive and those that restrict HIV-1. Regulation of hematopoietic cell kinase (Hck) activity and selective expression of CCAAT enhancer binding protein β (C/ EBPβ) isoforms greatly contribute to determine distinct susceptibility of MΦs to HIV-1. Resistance is attributable to reduced expression of Hck and augmented expression of an inhibitory small isoform of C/EBPβ. Derivatives of erythromycin A (EMA) EM201 and EM703 inhibit the replication of HIV-1 in tissue MΦs, at posttranscriptional and translational levels. We demonstrate that EM201 and EM703 convert tissue MΦs from HIV-1 susceptible to HIV-1 resistant through down-regulation of Hck and induction of small isoforms of C/EBPβ. These drugs inhibit p38MAPK activation which is expressed only in susceptible tissue MΦs. Activated CD4~+T cells stimulate the viral replication in HIV-1 resistant MΦs through down-regulation of small isoforms of C/EBPβ via activation of ERK1/2. EM201 and EM703 can inhibit the MAPK activation and inhibit the burst of viral replication produced when CD4~+T cells and MΦs interact. These EM derivatives may be highly beneficial for repression of residual HIV-1 in the lymphoreticular system of HIV-1-infected patients and offer great promise for the creation of new anti-HIV drugs for the future treatment of AIDS patients.
机译：巨噬细胞（MΦs）是HIV-1的主要来源，尤其是在结核病患者中。有允许的MΦ和限制HIV-1的MΦ。调节造血细胞激酶（Hck）活性和CCAAT增强子结合蛋白β（C /EBPβ）亚型的选择性表达在很大程度上决定了MΦ对HIV-1的易感性。抗性归因于Hck的表达减少和C /EBPβ的抑制性小亚型的表达增加。在转录后和翻译水平，红霉素A（EMA）EM201和EM703的衍生物抑制组织MΦ中HIV-1的复制。我们证明EM201和EM703通过下调Hck并诱导C /EBPβ小同种型从HIV-1耐药的HIV-1转化组织MΦs。这些药物抑制p38MAPK激活，仅在易感组织MΦs中表达。激活的CD4〜+ T细胞通过ERK1 / 2的激活下调C /EBPβ的小亚型，从而刺激HIV-1抗性MΦs中的病毒复制。 EM201和EM703可以抑制MAPK激活，并抑制CD4〜+ T细胞与MΦ相互作用时产生的病毒复制爆发。这些EM衍生物对于抑制HIV-1感染患者的淋巴网状系统中残留的HIV-1可能是非常有益的，并为开发新的抗HIV药物为艾滋病患者的未来治疗提供了广阔前景。

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