Human Immunodeficiency Virus-1 Latency Reversal via the Induction of Early Growth Response Protein 1 to Bypass Protein Kinase C Agonist-Associated Immune Activation.
Human Immunodeficiency Virus-1 Latency Reversal via the Induction of Early Growth Response Protein 1 to Bypass Protein Kinase C Agonist-Associated Immune Activation.
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DOI：
10.3389/fmicb.2022.836831
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发表时间：
2022
影响因子：
5.2
通讯作者：
Jiang G
中科院分区：
文献类型：
--
作者：
Wong LM;Li D;Tang Y;Méndez-Lagares G;Thompson GR 3rd;Hartigan-O'Connor DJ;Dandekar S;Jiang G
人类免疫缺陷病毒1型（HIV）由于在艾滋病病毒感染者（PLWH）体内存在潜伏病毒库，仍然是一项全球性的健康挑战。静息CD4 + T细胞中潜伏但具有复制能力的HIV无法仅通过抗逆转录病毒疗法（ART）清除。HIV治愈的一种方法是“激活并杀灭”策略，其中已应用潜伏期逆转剂（LRA）来破坏潜伏的HIV，期望通过病毒的细胞病变效应或免疫介导的清除作用根除HIV病毒库。蛋白激酶C激动剂（PKCα）是一类LRA，已在一定程度上显示出破坏潜伏HIV的能力。然而，PKCα在体内的毒性仍然是一个令人担忧的问题。早期生长反应蛋白1（EGR1）是潜伏期逆转过程中PKCα的下游靶点。在此，我们表明PKCα诱导EGR1，而EGR1直接驱动依赖Tat的HIV转录。白藜芦醇是一种在葡萄和多种植物中发现的天然植物抗毒素，它在体外的几种HIV潜伏期模型以及从接受ART治疗的艾滋病病毒感染者体内分离的CD4 + T细胞中诱导Egr1表达并破坏潜伏的HIV。在原代CD4 + T细胞中，白藜芦醇在其逆转潜伏期的剂量下不会诱导免疫激活，这表明靶向EGR1可能能够逆转潜伏期并避免PKCα诱导的免疫激活。
Human Immunodeficiency Virus-1 (HIV) remains a global health challenge due to the latent HIV reservoirs in people living with HIV (PLWH). Dormant yet replication competent HIV harbored in the resting CD4+ T cells cannot be purged by antiretroviral therapy (ART) alone. One approach of HIV cure is the “Kick and Kill” strategy where latency reversal agents (LRAs) have been implemented to disrupt latent HIV, expecting to eradicate HIV reservoirs by viral cytopathic effect or immune-mediated clearance. Protein Kinase C agonists (PKCa), a family of LRAs, have demonstrated the ability to disrupt latent HIV to an extent. However, the toxicity of PKCa remains a concern in vivo. Early growth response protein 1 (EGR1) is a downstream target of PKCa during latency reversal. Here, we show that PKCa induces EGR1 which directly drives Tat-dependent HIV transcription. Resveratrol, a natural phytoalexin found in grapes and various plants, induces Egr1 expression and disrupts latent HIV in several HIV latency models in vitro and in CD4+ T cells isolated from ART-suppressed PLWH ex vivo. In the primary CD4+ T cells, resveratrol does not induce immune activation at the dosage that it reverses latency, indicating that targeting EGR1 may be able to reverse latency and bypass PKCa-induced immune activation.