Targeting FOX03a with TIC10 to eradicate HIV-1 from CNS reservoirs

 描述(申请人提供)：尽管联合抗逆转录病毒疗法(ART)，HIV-1继续在淋巴、肠道和中枢神经系统(CNS)形成蓄水池。HIV-1脑储存库是一个长寿命细胞池，其中包括血管周围巨噬细胞和小胶质细胞，它们可以携带复制能力强的病毒。迫切需要能够有效消除这些中枢神经系统细胞中艾滋病毒的治疗干预措施。FOXO3a是一种对衰老和免疫动态平衡至关重要的强大转录因子，它为消除HIV-1宿主带来了希望。我们以前的文献已经证明，FOXO3a和细胞因子肿瘤坏死因子相关的凋亡诱导配体(TRAIL)靶向HIV-1感染的巨噬细胞进行凋亡。有趣的是，现有证据表明，在HIV-1入侵期间，中枢神经系统细胞中缺乏FOXO3a和TRAIL信号。FOXO3a信号和TRAIL表达的缺失可能在无意中促进了HIV-1脑库的形成。由于TRAIL的表达受FOXO3a转录调控，在HIV-1感染中枢神经系统的过程中，FOXO3a可能成为清除HIV-1感染的巨噬细胞和小胶质细胞的药物靶点。然而，由于缺乏候选药物，在中枢神经系统靶向FOXO3a是不可能的。最近的药物开发为TIC10，也被称为ONC201，提供了一个强大而稳定的小分子，可以激活FOXO3a并转录诱导TRAIL的表达。TIC10具有口服活性，可穿透血脑屏障。此外，TIC10已显示出有效的抗肿瘤作用，目前正在进行临床试验。因此，我们推测目标转录因子FOXO3a至TIC10将诱导抗病毒基因TRAIL的表达，并有效地清除中枢神经系统中的HIV-1储存库。我们将确定TIC10介导的FOXO3a激活对HIV-1感染的巨噬细胞和小胶质细胞的功能影响。此外，我们将评估TIC10介导的FOXO3a激活对HIV脑炎(HIVE)和人源化小鼠模型的中枢神经系统病毒载量和神经炎症的治疗效果。更重要的是，我们将确定TIC10在体外和体内是否与标准ART具有协同抗病毒作用。拟议的研究将提供重要的概念证明，即内源性FOXO3a可以被利用来对抗持续和潜在的HIV-1感染。该研究策略利用了最新的药物开发、CNS细胞的原代培养、实验室和原代活的HIV-1病毒株，以及蜂箱和人源化小鼠模型的技术。了解HIV-1感染的免疫控制与当前抗逆转录病毒治疗之间的相互作用将为HIV-1感染及其中枢神经系统并发症的治疗提供新的见解。

 DESCRIPTION (provided by applicant): Despite combination antiretroviral therapy (ART), HIV-1 continues to form reservoirs in lymphoid, gut and central nervous system (CNS). The HIV-1 brain reservoir is a pool of long-lived cells, which include perivascular macrophages and microglia that can harbor replication-competent virus. Therapeutic interventions that can effectively eliminate HIV in these CNS cells are urgently needed. FOXO3a, a powerful transcription factor critical for aging and immune homeostasis, offers hope to eliminate HIV-1 reservoirs. Our previous publications have demonstrated that FOXO3a and cytokine TNF-related apoptosis-inducing ligand (TRAIL) target HIV-1-infected macrophages for apoptosis. Interestingly, available evidence suggests that there is a lack of FOXO3a and TRAIL signaling in the CNS cells during HIV-1 invasion. The deficiency of FOXO3a signaling and TRAIL expression may inadvertently facilitate the forming of HIV-1 brain reservoirs. Because TRAIL expression is under transcription control of FOXO3a, FOXO3a may serve as a drug target to clear HIV-1- infected macrophage and microglia during HIV-1 infection of the CNS. However, targeting FOXO3a in the CNS has not been possible due to a lack of drugs candidates. Recent drug development has provided TIC10, also known as ONC201, as a potent and stable small molecule that can activate FOXO3a and transcriptionally induce TRAIL expression. TIC10 is orally active and can cross blood-brain barrier. Moreover, TIC10 has shown efficacious antitumor effect and is currently tested in clinical trials. Therefore, we hypothesize that targetig transcription factor FOXO3a through TIC10 will induce expression of antiviral gene TRAIL and effectively eradicate HIV-1 reservoirs in the CNS. We will determine the functional effects of TIC10-mediated FOXO3a activation on HIV-1-infected macrophages and microglia. Furthermore, we will assess the therapeutic benefit of TIC10-mediated FOXO3a activation toward CNS viral load and neuroinflammation in HIV encephalitis (HIVE) and humanized mouse models. More importantly, we will determine whether the TIC10 has synergistic antiviral effect with the standard ART both in vitro and in vivo. The proposed studies will provide important proof-of-concept that endogenous FOXO3a could be harnessed to combat persistent and latent HIV-1 infection. The research strategy takes advantage of the latest drug development, the primary CNS cell cultures, the laboratory and primary live HIV-1 viral strains, and the technologies of HIVE and humanized mouse models. Understanding the interactions between immune control of HIV-1 infection and current ART will reveal new insights for the treatment of HIV-1 infection and its CNS complications.