IRF7 expression correlates with HIV latency reversal upon specific blockade of immune activation.
IRF7 expression correlates with HIV latency reversal upon specific blockade of immune activation.
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DOI：
10.3389/fimmu.2022.1001068
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发表时间：
2022
影响因子：
7.3
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中科院分区：
文献类型：
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潜伏 HIV 储存库的持续存在使得抗逆转录病毒治疗中断后病毒反弹，从而阻碍 HIV-1 的有效治愈。新的证据表明，调节先天免疫刺激可能会影响病毒潜伏期，并有助于清除艾滋病毒储存库。在这里，选择性 JAK2 抑制剂亚类的潜伏再激活能力被描述为治疗 HIV-1 的潜在新型治疗策略。值得注意的是，JAK2 抑制剂在 HIV-1 潜伏期的体外非克隆淋巴和骨髓模型中逆转了 HIV-1 潜伏期，并且在来自 ART+ PWH 的 CD4+ T 细胞中也逆转了 HIV-1 潜伏期，尽管其功能不依赖于 JAK2 表达。免疫表型表征和全转录组分析支持重新激活数据，显示与其他 JAK 抑制剂相比，潜伏期重新激活剂（LRA、JAK2i fedratinib 和 PMA）之间存在共同的基因表达特征，但通路分析中受影响的基因组明显较少。对差异表达基因的深入评估发现，尽管 JAK-STAT 通路被阻断以及促炎细胞因子和趋化因子下调，但 IRF7 表达仍显着上调。此外，IRF7 表达水平与 JAK2 抑制剂和其他常见 LRA 的 HIV 潜伏期再激活能力呈正相关。总的来说，这些结果证明了先天免疫调节通过 IRF7 驱动的新途径减少病毒库的潜力，代表着朝着根除 HIV 迈出了有希望的一步。
The persistence of latent HIV reservoirs allows for viral rebound upon antiretroviral therapy interruption, hindering effective HIV-1 cure. Emerging evidence suggests that modulation of innate immune stimulation could impact viral latency and contribute to the clearing of HIV reservoir. Here, the latency reactivation capacity of a subclass of selective JAK2 inhibitors was characterized as a potential novel therapeutic strategy for HIV-1 cure. Notably, JAK2 inhibitors reversed HIV-1 latency in non-clonal lymphoid and myeloid in vitro models of HIV-1 latency and also ex vivo in CD4+ T cells from ART+ PWH, albeit its function was not dependent on JAK2 expression. Immunophenotypic characterization and whole transcriptomic profiling supported reactivation data, showing common gene expression signatures between latency reactivating agents (LRA; JAK2i fedratinib and PMA) in contrast to other JAK inhibitors, but with significantly fewer affected gene sets in the pathway analysis. In depth evaluation of differentially expressed genes, identified a significant upregulation of IRF7 expression despite the blockade of the JAK-STAT pathway and downregulation of proinflammatory cytokines and chemokines. Moreover, IRF7 expression levels positively correlated with HIV latency reactivation capacity of JAK2 inhibitors and also other common LRAs. Collectively, these results represent a promising step towards HIV eradication by demonstrating the potential of innate immune modulation for reducing the viral reservoir through a novel pathway driven by IRF7.