PNAS：抑制艾滋病病毒生命周期

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PNAS：抑制艾滋病病毒生命周期
HIV感染淋巴细胞

美国马里兰大学医学院科研人员报告说，抑制淋巴细胞中的mTORC-1 和mTORC-2这两种蛋白质复合体能够抑制艾滋病病毒进入细胞和表达其基因，并且减少了一个艾滋病病毒小鼠模型的血浆病毒水平，这提示了mTORC-1/-2的抑制可能有助于控制病人的艾滋病病毒，特别是对于那些感染了对目前抗逆转录病毒疗法具有耐性的毒株的病人。

艾滋病毒需要宿主因素成功完成其生命周期。雷帕霉素(mTOR)的目标是哺乳动物一个保守的丝氨酸/苏氨酸激酶， 这个激酶由mTORC1和mTORC2这两个亚基组成。雷帕霉素是mTOR一种变构抑制剂的选择性抑制mTORC1。雷帕霉素干扰病毒亲和受体CCR5(R5)和HIV LTR的基础转录，强效抑制R5-HIV复制，但不是在主细胞趋化因子受体CXCR4(X4)的艾滋病毒。最近开发的ATP竞争性mTOR激酶抑制剂(Tor KIS)能抑制mTORC1和mTORC2。使用TOR-KI为原型的ink128，我们可以看到有效抑制R5和X4艾滋病毒在初级淋巴细胞(EC50值<50 nm)中缺乏毒性。ink128还可以抑制R5 HIV进入的CCR5水平降低。INK128同时阻止了基质和hiv病毒的逆转录，与此同时限制了mTORC2,这亚基对蛋白激酶C亚型的磷酸化是至关重要的，反过来诱导NF-κB。INK128增强CCR5拮抗剂maraviroc的抗病毒能力,同样也与艾滋病毒逆转录酶抑制剂、整合酶和蛋白酶有良好的抗病毒的相互作用。在艾滋病病毒小鼠模型中，ink128使血浆HIV RNA的下降>lg2单位和部分恢复CD4/CD8细胞比值。ink128的细胞mTOR靶向(也许其他Tor KIS)提供了抑制HIV的潜在策略，特别是对于那些感染了对目前抗逆转录病毒疗法具有耐性的毒株的病人。

原文标题：Targeting of mTOR catalytic site inhibits multiple steps of the HIV-1 lifecycle and suppresses HIV-1 viremia in humanized mice

原文摘要：HIV necessitates host factors for successful completion of its life cycle. Mammalian target of rapamycin (mTOR) is a conserved serine/threonine kinase that forms two complexes, mTORC1 and mTORC2. Rapamycin is an allosteric inhibitor of mTOR that selectively inhibits mTORC1. Rapamycin interferes with viral entry of CCR5 (R5)-tropic HIV and with basal transcription of the HIV LTR, potently inhibiting replication of R5 HIV but not CXCR4 (X4)-tropic HIV in primary cells. The recently developed ATP-competitive mTOR kinase inhibitors (TOR-KIs) inhibit both mTORC1 and mTORC2. Using INK128 as a prototype TOR-KI, we demonstrate potent inhibition of both R5 and X4 HIV in primary lymphocytes (EC50 < 50 nM), in the absence of toxicity. INK128 inhibited R5 HIV entry by reducing CCR5 levels. INK128 also inhibited both basal and induced transcription of HIV genes, consistent with inhibition of mTORC2, whose activity is critical for phosphorylation of PKC isoforms and, in turn, induction of NF-κB. INK128 enhanced the antiviral potency of the CCR5 antagonist maraviroc, and had favorable antiviral interactions with HIV inhibitors of reverse transcriptase, integrase and protease. In humanized mice, INK128 decreased plasma HIV RNA by >2 log10 units and partially restored CD4/CD8 cell ratios. Targeting of cellular mTOR with INK128 (and perhaps others TOR-KIs) provides a potential strategy to inhibit HIV, especially in patients with drug resistant HIV strains.

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多谢大家最近一直在本版本发帖。俺老孙，上线了。。以后继续多多交流