Pharmacological Inhibition of IKK to Tackle Latency and Hyperinflammation in Chronic HIV-1 Infection.
Pharmacological Inhibition of IKK to Tackle Latency and Hyperinflammation in Chronic HIV-1 Infection.
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DOI：
10.3390/ijms232315000
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发表时间：
2022-11-30
影响因子：
5.6
通讯作者：
中科院分区：
文献类型：
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作者：
HIV潜伏感染可能与病毒RNA传感、干扰素（IFN）信号传导和/或IFN刺激基因（ISG）激活被破坏有关。在此，我们评估了选择性靶向核因子-κB（IκB）激酶（IKK）复合物亚基和相关激酶（TBK 1）抑制剂的化合物作为逆转潜伏感染的非克隆淋巴和骨髓细胞体外模型中HIV-1潜伏期的新途径的用途。IKK抑制剂（IKKis）在骨髓和淋巴细胞模型中引发了高达1.8倍的HIV再活化增加。分别靶向TBK-1（MRT 67307）和IKKβ（TCPA-1）的同类最佳IKK也能够显著诱导来自HIV感染者（PLWH）的CD 4 + T细胞中的病毒再活化。更重要的是，虽然没有测试的化合物显示抗病毒活性，不同IKKIs与ART的组合不影响潜伏期的再激活，也不阻断HIV感染的ART。最后，正如预期的那样，IKKIs没有上调细胞活化标记物在初级淋巴细胞和先天免疫信号被阻断，导致炎症细胞因子的下调。总的来说，我们的研究结果支持IKKis作为免疫调节剂的双重作用，能够解决淋巴和骨髓细胞模型中的HIV潜伏库，并且能够控制慢性HIV-1感染中的炎症反应。
HIV latent infection may be associated with disrupted viral RNA sensing, interferon (IFN) signaling, and/or IFN stimulating genes (ISG) activation. Here, we evaluated the use of compounds selectively targeting at the inhibitor of nuclear factor-κB (IκB) kinase (IKK) complex subunits and related kinases (TBK1) as a novel pathway to reverse HIV-1 latency in latently infected non-clonal lymphoid and myeloid cell in vitro models. IKK inhibitors (IKKis) triggered up to a 1.8-fold increase in HIV reactivation in both, myeloid and lymphoid cell models. The best-in-class IKKis, targeting TBK-1 (MRT67307) and IKKβ (TCPA-1) respectively, were also able to significantly induce viral reactivation in CD4+ T cells from people living with HIV (PLWH) ex vivo. More importantly, although none of the compounds tested showed antiviral activity, the combination of the distinct IKKis with ART did not affect the latency reactivation nor blockade of HIV infection by ART. Finally, as expected, IKKis did not upregulate cell activation markers in primary lymphocytes and innate immune signaling was blocked, resulting in downregulation of inflammatory cytokines. Overall, our results support a dual role of IKKis as immune modulators being able to tackle the HIV latent reservoir in lymphoid and myeloid cellular models and putatively control the hyperinflammatory responses in chronic HIV-1 infection.
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