The inhibitor apoptosis protein antagonist Debio 1143 Is an attractive HIV-1 latency reversal candidate
The inhibitor apoptosis protein antagonist Debio 1143 Is an attractive HIV-1 latency reversal candidate
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DOI：
10.1371/journal.pone.0211746
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发表时间：
2019-02-04
期刊：
影响因子：
3.7
通讯作者：
Gallay, Philippe A.
中科院分区：
文献类型：
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作者：
Bobardt, Michael;Kuo, Joseph;Gallay, Philippe A.
抗逆转录病毒疗法(ART)抑制艾滋病毒复制，但不能治愈感染，因为在多年的治疗中，具有复制能力的病毒持续存在于潜伏感染的CD4+T细胞中。这些储存库包含整合的HIV-1基因组，可以为活跃的病毒提供再补给。因此，制定消除潜伏感染细胞储存库的策略是具有全球意义的研究重点。在这项研究中，我们测试了一种新的凋亡抑制蛋白拮抗剂(IAPA)Debio 1143逆转HIV潜伏期的效果，并探讨了其作用机制。Debio 1143通过降解泛素连接酶杆状病毒IAP重复序列2(BIRC2)来激活HIV转录，BIRC2是非规范的NF-kB途径的抑制子。Debio 1143诱导的BIRC2降解导致核因子-KB诱导激酶(NIK)的积聚和P100的蛋白水解性裂解成p52，导致p52和RELB的核移位。Debio 1143极大地增强了RELB与HIV-1 LTR的结合。这些数据表明，Debio 1143通过促进RELB：P52复合体与HIV-1 LTR结合，激活依赖LTR的HIV-1转录，激活了非规范的NF-kB信号通路。重要的是，Debio 1143逆转了HIV-1潜伏T细胞系中的病毒潜伏期。使用敲除(SiRNA BIRC2)、敲除(CRIPSR Nik)和蛋白酶体机械中和(MG132)方法，我们发现Debio 1143介导的HIV潜伏期逆转是BIRC2降解和Nik稳定依赖的。Debio 1143还逆转了来自ART治疗患者或在ART下感染HIV-1的人源化小鼠的静止CD4+T细胞中的HIV-1潜伏期。有趣的是，癌症患者在耐受性良好的剂量下每天口服Debio 1143可诱导PBMCs中BIRC2靶点的参与，并诱导与NF-kB信号机制相关的细胞因子和趋化因子适度增加。总之，我们提供了强有力的证据表明，IAPA Debio 1143通过最初激活非规范的NF-kB信号，随后重新激活HIV-1转录，代表了一种新的有吸引力的病毒潜伏期反转剂(LRA)。
Antiretroviral therapy (ART) suppresses HIV replication, but does not cure the infection because replication-competent virus persists within latently infected CD4+ T cells throughout years of therapy. These reservoirs contain integrated HIV-1 genomes and can resupply active virus. Thus, the development of strategies to eliminate the reservoir of latently infected cells is a research priority of global significance. In this study, we tested efficacy of a new inhibitor of apoptosis protein antagonist (IAPa) called Debio 1143 at reversing HIV latency and investigated its mechanisms of action. Debio 1143 activates HIV transcription via NF-kB signaling by degrading the ubiquitin ligase baculoviral IAP repeat-containing 2 (BIRC2), a repressor of the non-canonical NF-kB pathway. Debio 1143-induced BIRC2 degradation results in the accumulation of NF-KB-inducing kinase (NIK) and proteolytic cleavage of p100 into p52, leading to nuclear translocation of p52 and RELB. Debio 1143 greatly enhances the binding of RELB to the HIV-1 LTR. These data indicate that Debio 1143 activates the non-canonical NF-kB signaling pathway by promoting the binding of RELB:p52 complexes to the HIV-1 LTR, resulting in the activation of the LTR-dependent HIV-1 transcription. Importantly, Debio 1143 reverses viral latency in HIV-1 latent T cell lines. Using knockdown (siRNA BIRC2), knockout (CRIPSR NIK) and proteasome machinery neutralization (MG132) approaches, we found that Debio 1143-mediated HIV latency reversal is BIRC2 degradation- and NIK stabilization-dependent. Debio 1143 also reverses HIV-1 latency in resting CD4+ T cells derived from ART-treated patients or HIV-1-infected humanized mice under ART. Interestingly, daily oral administration of Debio 1143 in cancer patients at well-tolerated doses elicited BIRC2 target engagement in PBMCs and induced a moderate increase in cytokines and chemokines mechanistically related to NF-kB signaling. In conclusion, we provide strong evidences that the IAPa Debio 1143, by initially activating the non-canonical NF-kB signaling and subsequently reactivating HIV-1 transcription, represents a new attractive viral latency reversal agent (LRA).