Nuffield Department of Clinical Medicine, University of Oxford, Oxford, UK.
Department of Pharmacology, University of Oxford, Oxford, UK.
J Gen Virol. 2023 Aug;104(8). doi: 10.1099/jgv.0.001877.
Human immunodeficiency virus type 1 (HIV-1) causes a major burden on global health, and eradication of latent virus infection is one of the biggest challenges in the field. The circadian clock is an endogenous timing system that oscillates with a ~24 h period regulating multiple physiological processes and cellular functions, and we recently reported that the cell intrinsic clock regulates rhythmic HIV-1 replication. Salt inducible kinases (SIK) contribute to circadian regulatory networks, however, there is limited evidence for SIKs regulating HIV-1 infection. Here, we show that pharmacological inhibition of SIKs perturbed the cellular clock and reduced rhythmic HIV-1 replication in circadian synchronised cells. Further, SIK inhibitors or genetic silencing of expression inhibited viral replication in primary cells and in a latency model, respectively. Overall, this study demonstrates a role for salt inducible kinases in regulating HIV-1 replication and latency reactivation, which can provide innovative routes to better understand and target latent HIV-1 infection.
人类免疫缺陷病毒 1 型（HIV-1）对全球健康造成了重大负担，根除潜伏病毒感染是该领域面临的最大挑战之一。生物钟是一种内源性计时系统，以约 24 小时的周期振荡，调节多种生理过程和细胞功能，我们最近报道细胞内固有时钟调节 HIV-1 的节律性复制。盐诱导激酶（SIK）有助于生物钟调节网络，但 SIK 调节 HIV-1 感染的证据有限。在这里，我们表明，SIK 的药理学抑制扰乱了细胞时钟，并减少了节律性同步细胞中 HIV-1 的复制。此外，SIK 抑制剂或表达的基因沉默分别抑制了原代细胞和潜伏模型中的病毒复制。总的来说，这项研究表明盐诱导激酶在调节 HIV-1 复制和潜伏病毒激活方面发挥作用，这可以为更好地理解和靶向潜伏 HIV-1 感染提供创新途径。
