State Key Laboratory of Genetic Evolution & Animal Models, Key Laboratory of Bioactive Peptides of Yunnan Province, KIZ-CUHK Joint Laboratory of Bioresources and Molecular Research in Common Diseases, Center for Biosafety Mega-Science, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan, China.
University of Chinese Academy of Sciences, Beijing, China.
J Virol. 2024 Nov 19;98(11):e0135624. doi: 10.1128/jvi.01356-24. Epub 2024 Oct 30.
Type I interferon (IFN-I) and its downstream genes play a profound role in HIV infection. In this study, we found that an IFN-inducible gene, IFI27, was upregulated in HIV-1 infection, which in turn efficiently suppressed HIV-1 replication, specially degraded the viral gag protein, including p24 and p55 subunits. Notably, the anti-HIV-1 activity of IFI27 in Old World monkeys surpassed that in New World monkeys, and IFI27 has a higher potentially inhibitory effect on HIV-1 than simian immunodeficiency virus (SIV). Our initial observations showed that NPM-IFI27, the IFI27 variant in northern pig-tailed macaque (, NPM), exhibited a strong anti-HIV-1 activity. Further investigation demonstrated that NPM-IFI27 degraded p24 and p55 via the ubiquitin-proteasome pathway, with NPM-IFI27-37-115 interacting with the p24-N domain, and the NPM-IFI27-76-122 domain was closely associated with K48 ubiquitin recruitment. Additionally, Skp2 was identified as the probable E3 ubiquitin ligase responsible for the degradation of p24 and p55. Similarly, human IFI27 (Hu-IFI27) showed a mechanism similar to NPM-IFI27 in HIV-1 inhibition. These findings underscore the pivotal role of NPM-IFI27 in HIV-1 infection and provide a potential strategy for clinical anti-HIV-1 therapy.IMPORTANCEHIV-1 infection can trigger the production of IFN-I, which subsequently activates the expression of various IFN-stimulated genes (ISGs) to antagonize the virus. Therefore, discovering novel host antiviral agents for HIV-1 treatment is crucial. Our previous study revealed that IFI27 can influence HIV-1 replication. In this study, we observed that the NPM-IFI27 complex specifically inhibited HIV-1 by targeting its Gag protein. Further exploration demonstrated that IFI27 interacted with the HIV-1 p24 and p55 proteins, leading to their degradation through the ubiquitin-proteasome pathway. Notably, the NPM-IFI27-37-122 variant exhibited potent anti-HIV-1 activity, comparable to that of SAMHD1. These findings highlight the critical role and inhibitory mechanism of NPM-IFI27 in HIV-1 infection, providing a potential strategy for clinical antiviral therapy.
I 型干扰素（IFN-I）及其下游基因在 HIV 感染中发挥着深远的作用。在这项研究中，我们发现 HIV-1 感染会诱导干扰素诱导基因 IFI27 的表达上调，进而有效地抑制 HIV-1 的复制，特别是降解病毒 gag 蛋白，包括 p24 和 p55 亚基。值得注意的是，IFI27 在旧世界猴中的抗 HIV-1 活性超过了新世界猴，并且 IFI27 对 HIV-1 的潜在抑制作用高于猴免疫缺陷病毒（SIV）。我们的初步观察表明，来自北方猪尾猕猴（NPM）的 IFI27 变体 NPM-IFI27 表现出强烈的抗 HIV-1 活性。进一步的研究表明，NPM-IFI27 通过泛素蛋白酶体途径降解 p24 和 p55，其中 NPM-IFI27-37-115 与 p24-N 结构域相互作用，而 NPM-IFI27-76-122 结构域与 K48 泛素募集密切相关。此外，Skp2 被鉴定为负责降解 p24 和 p55 的可能 E3 泛素连接酶。同样，人 IFI27（Hu-IFI27）在 HIV-1 抑制中表现出与 NPM-IFI27 相似的机制。这些发现强调了 NPM-IFI27 在 HIV-1 感染中的关键作用，并为临床抗 HIV-1 治疗提供了一种潜在策略。
HIV-1 感染可引发 IFN-I 的产生，随后激活各种干扰素刺激基因（ISGs）的表达，以拮抗病毒。因此，发现用于 HIV-1 治疗的新型宿主抗病毒药物至关重要。我们之前的研究表明 IFI27 可以影响 HIV-1 的复制。在这项研究中，我们观察到 NPM-IFI27 复合物通过靶向其 gag 蛋白特异性抑制 HIV-1。进一步的探索表明，IFI27 与 HIV-1 p24 和 p55 蛋白相互作用，导致它们通过泛素蛋白酶体途径降解。值得注意的是，NPM-IFI27-37-122 变体表现出强大的抗 HIV-1 活性，与 SAMHD1 相当。这些发现强调了 NPM-IFI27 在 HIV-1 感染中的关键作用和抑制机制，为临床抗病毒治疗提供了一种潜在策略。
