Small Molecule Inhibitors of BAF; A Promising Family of Compounds in HIV-1 Latency Reversal.
Small Molecule Inhibitors of BAF; A Promising Family of Compounds in HIV-1 Latency Reversal.
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DOI：
10.1016/j.ebiom.2015.11.047
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发表时间：
2016-01
期刊：
影响因子：
11.1
通讯作者：
Mahmoudi T
中科院分区：
文献类型：
--
作者：
Stoszko M;De Crignis E;Rokx C;Khalid MM;Lungu C;Palstra RJ;Kan TW;Boucher C;Verbon A;Dykhuizen EC;Mahmoudi T
抗逆转录病毒治疗中潜伏感染细胞的持续存在是根除 HIV-1 的主要障碍。因此，人们投入了大量精力来鉴定能够逆转 HIV-1 潜伏期的化合物，以使受感染的细胞容易受到病毒细胞病变作用和免疫清除的影响。我们确定 BAF 染色质重塑复合物是维持 HIV-1 潜伏期所需的关键参与者，强调了其作为抑制潜伏期逆转的分子靶标的潜力。在这里，我们筛选了一组最近鉴定的 BAF 小分子抑制剂 (BAFi's)，以了解其激活潜在 HIV-1 的潜力。 BAFi 的咖啡酸苯乙酯和乙胺嘧啶强烈诱导延迟逆转，这两种分子先前已被用于临床应用。 BAFi 在基于细胞系的潜伏期模型、两种离体感染的原代细胞潜伏期模型以及 HIV-1 感染患者的 CD4 + T 细胞中逆转了 HIV-1 潜伏期，且不诱导 T 细胞增殖或激活。 BAFi 诱导的 HIV-1 潜伏期逆转在 PKC 通路激活和 HDAC 抑制时协同增强。因此，BAFi 构成了一个有前途的分子家族，可用于治疗组合 HIV-1 潜伏期逆转。 BAF 复合物抑制剂 (BAFi) 可激活潜伏细胞系模型中的潜伏 HIV-1。 BAFi 与 HDAC 抑制剂和 PKC 激活剂结合可协同激活潜伏的 HIV-1。 BAFi 的 PYR 和 CAPE 可逆转原代细胞潜伏期模型和从 HIV-1 患者获得的细胞中的 HIV-1 潜伏期。联合抗逆转录病毒疗法 (cART) 使 HIV-1 感染成为一种慢性疾病。然而，cART 并不能治愈，因为尽管有 cART，仍有少量携带沉默病毒且有可能重新感染的受感染细胞持续存在。治愈 HIV-1 的努力包括激活这些潜伏细胞，使它们易于被免疫清除。在这里，我们描述了 BAF 抑制剂在 HIV-1 潜伏期体外模型以及从 HIV-1 感染患者志愿者获得的细胞中激活 HIV-1 的活性。我们的数据强调了 BAF 抑制剂纳入组合疗法以逆转 HIV-1 潜伏期的临床潜力。
Persistence of latently infected cells in presence of Anti-Retroviral Therapy presents the main obstacle to HIV-1 eradication. Much effort is thus placed on identification of compounds capable of HIV-1 latency reversal in order to render infected cells susceptible to viral cytopathic effects and immune clearance. We identified the BAF chromatin remodeling complex as a key player required for maintenance of HIV-1 latency, highlighting its potential as a molecular target for inhibition in latency reversal. Here, we screened a recently identified panel of small molecule inhibitors of BAF (BAFi's) for potential to activate latent HIV-1. Latency reversal was strongly induced by BAFi's Caffeic Acid Phenethyl Ester and Pyrimethamine, two molecules previously characterized for clinical application. BAFi's reversed HIV-1 latency in cell line based latency models, in two ex vivo infected primary cell models of latency, as well as in HIV-1 infected patient's CD4 + T cells, without inducing T cell proliferation or activation. BAFi-induced HIV-1 latency reversal was synergistically enhanced upon PKC pathway activation and HDAC-inhibition. Therefore BAFi's constitute a promising family of molecules for inclusion in therapeutic combinatorial HIV-1 latency reversal. BAF complex inhibitors (BAFi's) activate latent HIV-1 in cell line models of latency. BAFi's in combination with HDAC inhibitors and PKC activators synergistically activate latent HIV-1. The BAFi's PYR and CAPE reverse HIV-1 latency in primary cell models of latency and in cells obtained from HIV-1 patients. Access to Combination antiretroviral therapy (cART) has made HIV-1 infection a chronic disease. However, cART is not curative, as a small number of infected cells harboring silent virus with potential to renew the infection persist despite cART. Efforts to cure HIV-1 include activation of these latent cells, making them susceptible to immune clearance. Here we describe the activity of BAF inhibitors in HIV-1 activation in in vitro models of HIV-1 latency as well as in cells obtained from HIV-1 infected patient volunteers. Our data highlight the clinical potential of BAF inhibitors for inclusion in combinatorial therapy to reverse HIV-1 latency.