Targeting of mTOR catalytic site inhibits multiple steps of the HIV-1 lifecycle and suppresses HIV-1 viremia in humanized mice
Targeting of mTOR catalytic site inhibits multiple steps of the HIV-1 lifecycle and suppresses HIV-1 viremia in humanized mice
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DOI：
10.1073/pnas.1511144112
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发表时间：
2015-07-28
影响因子：
11.1
通讯作者：
Redfield, Robert R.
中科院分区：
文献类型：
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作者：
Heredia, Alonso;Le, Nhut;Redfield, Robert R.
艾滋病毒需要宿主因素才能成功完成其生命周期。雷帕霉素的哺乳动物靶标(MTOR)是一种保守的丝氨酸/苏氨酸激酶，形成两个复合体mTORC1和mTORC2。雷帕霉素是一种mTOR的变构抑制剂，选择性地抑制mTORC1。雷帕霉素干扰嗜CCR5(R5)的HIV病毒进入和HIV LTR的基础转录，有效地抑制R5 HIV的复制，但不能抑制CXCR4(X4)嗜性的HIV在原代细胞中的复制。最近开发的ATP竞争性mTOR激酶抑制剂(TOR-Kis)对mTORC1和mTORC2都有抑制作用。使用INK128作为TOR-KI的原型，我们证明了在没有毒性的情况下，对初级淋巴细胞(EC50和50 nm)中的R5和X4艾滋病毒都有有效的抑制作用。INK128通过降低CCR5水平来抑制R5 HIV进入。INK128还抑制HIV基因的基础转录和诱导转录，这与对mTORC2的抑制一致，mTORC2的活性对PKC亚型的磷酸化至关重要，进而诱导NF-kappa B的诱导。INK128增强了CCR5拮抗剂马拉韦罗的抗病毒效力，并与逆转录酶、整合酶和蛋白酶的HIV抑制剂具有良好的抗病毒作用。在人源化小鼠中，INK128将血浆HIV RNA降低了2log10个单位，并部分恢复了CD4/CD8细胞比率。用INK128(也许还有其他TOR-Kis)靶向细胞mTOR提供了一种潜在的抑制HIV的策略，特别是在具有抗药性的HIV毒株的患者中。
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-kappa B. INK128 enhanced the antiviral potency of the CCR5 antagonistmaraviroc, 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.