Reactivation of HIV latency by a newly modified Ingenol derivative via protein kinase Cδ-NF-κB signaling.
Reactivation of HIV latency by a newly modified Ingenol derivative via protein kinase Cδ-NF-κB signaling.
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DOI：
10.1097/qad.0000000000000289
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发表时间：
2014-07-17
期刊：
影响因子：
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通讯作者：
Dandekar S
中科院分区：
文献类型：
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作者：
Jiang G;Mendes EA;Kaiser P;Sankaran-Walters S;Tang Y;Weber MG;Melcher GP;Thompson GR 3rd;Tanuri A;Pianowski LF;Wong JK;Dandekar S
虽然HAART有效地抑制病毒复制，但它不能根除潜伏的病毒库。“休克和杀死”战略涉及从潜伏的宿主中激活艾滋病毒，并将其作为根除目标。我们的目标是开发新的方法，从潜伏的水库激活艾滋病毒。我们研究了Ingenol B（IngB）的能力，Ingenol酯的一种新的修饰衍生物，最初是从巴西亚马逊的一种植物中分离出来的，其HIV再激活的能力和机制。在HIV潜伏期的J-Lat A1细胞培养模型中以及在来自长期HAART治疗的病毒学抑制的HIV感染个体的纯化的原代CD 4 + T细胞中评价了IngB对HIV-1的再活化。使用流式细胞术、RT-qPCR和染色质免疫沉淀研究了病毒再活化的潜在分子机制。IngB在重新激活J-Lat A1细胞中的HIV方面非常有效，细胞毒性相对较低。它也能够重新激活潜伏的HIV在纯化的CD 4 + T细胞从HAART治疗的HIV阳性个体离体。我们的数据表明，IngB可能通过激活活化B细胞的蛋白激酶C（PKC）δ-核因子κ轻链增强子（NF-κB）途径和直接诱导NF-κB蛋白表达来重新激活HIV表达。重要的是，IngB与BET布罗莫结构域抑制剂JQ 1在潜伏的HIV再活化中具有协同效应。IngB是一种新的有前途的化合物，可以激活潜伏的HIV储库。我们的数据表明，从Ingenol酯中制备新型衍生物可能是开发新的先导化合物以重新激活潜伏的HIV的创新方法。
Although HAART effectively suppresses viral replication, it fails to eradicate latent viral reservoirs. The ‘shock and kill’ strategy involves the activation of HIV from latent reservoirs and targeting them for eradication. Our goal was to develop new approaches for activating HIV from latent reservoirs. We investigated capacity of Ingenol B (IngB), a newly modified derivative of Ingenol ester that was originally isolated from a Brazilian plant in Amazon, for its capacity and mechanisms of HIV reactivation. Reactivation of HIV-1 by IngB was evaluated in J-Lat A1 cell culture model of HIV latency as well as in purified primary CD4+ T cells from long-term HAART-treated virologically-suppressed HIV-infected individuals. The underlining molecular mechanisms of viral reactivation were investigated using flow cytometry, RT-qPCR and chromatin immunoprecipitation. IngB is highly effective in reactivating HIV in J-Lat A1 cells with relatively low cellular toxicity. It is also able to reactivate latent HIV in purified CD4+ T cells from HAART-treated HIV-positive individuals ex vivo. Our data show that IngB may reactivate HIV expression by both activating protein kinase C (PKC)δ–nuclear factor kappalight-chain-enhancer of activated B cells (NF-κB) pathway and directly inducing NF-κB protein expression. Importantly, IngB has a synergistic effect with JQ1, a BET bromodomain inhibitor, in latent HIV reactivation. IngB is a new promising compound to activate latent HIV reservoirs. Our data suggest that formulating novel derivatives from Ingenol esters may be an innovative approach to develop new lead compounds to reactivate latent HIV.