PLOS Pathogens:同期两篇文章分别报道发现可激活潜伏HIV药物

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人类免疫缺陷病毒（Human Immunodeficiency Virus或HIV），造成人类免疫系统的缺陷的一种病毒。1983年，人类免疫缺陷病毒在美国首次发现。它是一种感染人类免疫系统细胞的慢病毒（Lentivirus），属逆转录病毒的一种。至今无有效疗法的致命性传染病。该病毒破坏人体的免疫能力，导致免疫系统失去抵抗力，从而导致各种疾病及癌症。


当 HIV 感染免疫细胞之时，它会将自身的遗传物质插入到感染细胞的 DNA 中。在大多数的情况下，病毒感染细胞后会在细胞内进行大量的扩增，新病毒从感染细胞中释放出来，会扩散感染机体其他的免疫细胞。然而，在某些情况下， HIV 表达会进入等待模式，感染免疫细胞内的病毒进入到一种潜伏状态，意味着有一小部分的 HIV 匿藏在感染细胞中，这是用抗逆转录药物治疗（HAART）HIV所面临的困境。因此，通过药物诱导这些潜伏感染细胞中HIV基因表达激活，从而消灭这些“HIV储存库”是目前最具前景的治疗手段。这种被成为“休克和死亡”的治疗策略吸引了全世界的HIV科学家。


近日，在PLOS Pathogens上，同期发表了两篇文章报道了这类药物的筛选。


第一篇是来自比利时布鲁塞尔自由大学Carine Van Lint教授实验室。研究人员发现细胞蛋白激酶C（PKC）的激动剂(prostratin, bryostatin-1 and ing-B)和正性转录延伸因子b（P-TEFb）的激动剂 (HMBA and BETi (JQ1, I-BET, I-BET151))具有激活潜伏HIV的能力。同时，两种药物的联合使用（ bryostatin-1+JQ1 和ingenol-B+JQ1 ）在体外细胞系和来自病人的原代细胞上证实具有非常好的潜伏HIV激活效果。





第二篇文章是由来自美国加利福尼亚大学的Satya Dandekar教授实验室。研究人员发现一小分子PEP005能够高效激活潜伏HIV。这一小分子是FDA批准的用于治疗光化性角化病（皮肤癌的癌前病变）的药物PICATO的活性成分。另外，Satya Dandekar教授还发现当PEP005与P-TEFb 激动剂 JQ1联合使用时(PEP005+JQ1)，其激活效果比PEP005单独使用时强7.5倍。





这些研究向着彻底消灭HIV的方向迈进了一大步。特别是这些已经通过FDA批准的药物，可以避免长时间的临床试验，快速推进到临床治疗中。

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An In-Depth Comparison of Latency-Reversing Agent Combinations in Various In Vitro and Ex Vivo HIV-1 Latency Models Identified Bryostatin-1+JQ1 and Ingenol-B+JQ1 to Potently Reactivate Viral Gene Expression

Gilles Darcis , Anna Kula , Sophie Bouchat, Koh Fujinaga, Francis Corazza, Amina Ait-Ammar, Nadège Delacourt, Adeline Melard, Kabamba Kabeya, Caroline Vanhulle, Benoit Van Driessche, Jean-Stéphane Gatot, Thomas Cherrier, Luiz F. Pianowski, Lucio Gama, Christian Schwartz, Jorge Vila, Arsène Burny, Nathan Clumeck, Michel Moutschen, Stéphane De Wit, B. Matija Peterlin, Christine Rouzioux, Olivier Rohr , Carine Van Lint

Abstract

The persistence of latently infected cells in patients under combinatory antiretroviral therapy (cART) is a major hurdle to HIV-1 eradication. Strategies to purge these reservoirs are needed and activation of viral gene expression in latently infected cells is one promising strategy. Bromodomain and Extraterminal (BET) bromodomain inhibitors (BETi) are compounds able to reactivate latent proviruses in a positive transcription elongation factor b (P-TEFb)-dependent manner. In this study, we tested the reactivation potential of protein kinase C (PKC) agonists (prostratin, bryostatin-1 and ingenol-B), which are known to activate NF-κB signaling pathway as well as P-TEFb, used alone or in combination with P-TEFb-releasing agents (HMBA and BETi (JQ1, I-BET, I-BET151)). Using in vitro HIV-1 post-integration latency model cell lines of T-lymphoid and myeloid lineages, we demonstrated that PKC agonists and P-TEFb-releasing agents alone acted as potent latency-reversing agents (LRAs) and that their combinations led to synergistic activation of HIV-1 expression at the viral mRNA and protein levels. Mechanistically, combined treatments led to higher activations of P-TEFb and NF-κB than the corresponding individual drug treatments. Importantly, we observed in ex vivo cultures of CD8+-depleted PBMCs from 35 cART-treated HIV-1+ aviremic patients that the percentage of reactivated cultures following combinatory bryostatin-1+JQ1 treatment was identical to the percentage observed with anti-CD3+anti-CD28 antibodies positive control stimulation. Remarkably, in ex vivo cultures of resting CD4+ T cells isolated from 15 HIV-1+ cART-treated aviremic patients, the combinations bryostatin-1+JQ1 and ingenol-B+JQ1 released infectious viruses to levels similar to that obtained with the positive control stimulation. The potent effects of these two combination treatments were already detected 24 hours post-stimulation. These results constitute the first demonstration of LRA combinations exhibiting such a potent effect and represent a proof-of-concept for the co-administration of two different types of LRAs as a potential strategy to reduce the size of the latent HIV-1 reservoirs.

http://journals.plos.org/plospat ... ournal.ppat.1005063

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Synergistic Reactivation of Latent HIV Expression by Ingenol-3-Angelate, PEP005, Targeted NF-kB Signaling in Combination with JQ1 Induced p-TEFb Activation

Guochun Jiang, Erica A. Mendes, Philipp Kaiser, Daniel P. Wong, Yuyang Tang, Ivy Cai, Anne Fenton, Gregory P. Melcher, James E. K. Hildreth, George R. Thompson, Joseph K. Wong, Satya Dandekar

Abstract
Although anti-retroviral therapy (ART) is highly effective in suppressing HIV replication, it fails to eradicate the virus from HIV-infected individuals. Stable latent HIV reservoirs are rapidly established early after HIV infection. Therefore, effective strategies for eradication of the HIV reservoirs are urgently needed. We report that ingenol-3-angelate (PEP005), the only active component in a previously FDA approved drug (PICATO) for the topical treatment of precancerous actinic keratosis, can effectively reactivate latent HIV in vitro and ex vivo with relatively low cellular toxicity. Biochemical analysis showed that PEP005 reactivated latent HIV through the induction of the pS643/S676-PKCδ/θ-IκBα/ε-NF-κB signaling pathway. Importantly, PEP005 alone was sufficient to induce expression of fully elongated and processed HIV RNAs in primary CD4+ T cells from HIV infected individuals receiving suppressive ART. Furthermore, PEP005 and the P-TEFb agonist, JQ1, exhibited synergism in reactivation of latent HIV with a combined effect that is 7.5-fold higher than the effect of PEP005 alone. Conversely, PEP005 suppressed HIV infection of primary CD4+ T cells through down-modulation of cell surface expression of HIV co-receptors. This anti-cancer compound is a potential candidate for advancing HIV eradication strategies.

http://journals.plos.org/plospat ... ournal.ppat.1005066