Suppressing the latent reservoir with a Tat inhibitor

 产品说明：尽管抗逆转录病毒疗法（ART）在将艾滋病毒复制降低到非常低的水平方面取得了巨大成功，但它未能根除病毒。HIV-1仍然存在于接受抑制性ART的个体中潜伏感染的记忆CD 4 + T细胞中，这些细胞代表了ART中断后复活病毒的持久来源。最常探索的HIV根除策略被称为“休克和杀死”，其试图使用抗潜伏剂如HDAC抑制剂清除病毒储库，同时通过维持ART来防止额外的感染。其他几种策略已用于根除潜伏的HIV-1储库，包括ART强化，治疗性疫苗，基因治疗和干细胞移植。每种方法都有其固有的挑战，没有一种方法取得了决定性的成功。 另一种方法是使用靶向HIV-1转录的治疗剂，这与根除潜伏性储库的既定范例有很大不同。而不是激活内源性潜伏水库，我们建议驱动残留的转录发生在ART进入长期潜伏或深潜伏状态。我们基于最近的发现，双脱氢皮质抑素A（dCA），一种类似物的天然化合物分离自海绵，有效地抑制Tat介导的反式激活的整合HIV-1启动子在纳摩尔浓度的建议。重要的是，dCA驱动病毒基因表达进入体外持续深潜伏期的诱导状态，对病毒再活化无效。一个Tat-抑制剂治疗结合ART的目的是通过阻断正在进行的病毒复制，再激活和补充的潜伏病毒库，一个关键的限制currnt ART。在这里，我们建议测试dCA在感染猴免疫缺陷病毒（SIV）的恒河猴的大小。我们假设，通过减少来自储库的持续、低水平病毒产生，dCA将i）通过防止其持续补充来减少病毒储库的大小，ii）防止或至少显著延迟ART停止后的病毒反弹，和iii）降低与由低-在R21项目阶段，我们将验证dCA可以有效地用于阻断SIV在原代恒河猴CD 4+淋巴细胞中的转录。在成功完成R21里程碑后，我们将启动该项目的R33阶段，旨在确定dCA与ART联合使用的影响，以及一旦病毒被转录抑制，dCA是否可以取代ART。

 DESCRIPTION: Despite the immense success of anti-retroviral therapy (ART) in reducing HIV replication to very low levels, it fails to eradicate the virus. HIV-1 still persists in latently ifected memory CD4+ T cells in individuals on suppressive ART and these cells represent a long-lasting source of resurgent virus upon ART interruption. The most commonly explored strategy for HIV eradication is dubbed "shock and kill", which attempts to purge viral reservoirs using anti-latency agents such as HDAC inhibitors, while simultaneously preventing additional rounds of infection by maintaining ART. Several other strategies have been employed for eradicating the latent HIV-1 reservoir including ART intensification, therapeutic vaccines, gene therapy, and stem cell transplantation. Each approach has its own inherent challenges and none have demonstrated definitive success. An alternative approach, which represents a significant departure from established paradigms of eradicating latent reservoirs, uses therapeutic agents targeting HIV-1 transcription. Rather than activating the endogenous latent reservoir, we propose to drive the residual transcription that occurs during ART into a state of long-term latency or deep latency. We based this proposal on the recent discovery that didehydro-Cortistatin A (dCA), an analog of a natural compound isolated from a marine sponge, potently inhibits Tat-mediated trans-activation of the integrated HIV-1 promoter at nanomolar concentrations. Importantly, dCA drives viral gene expression into an induced state of persistent deep-latency in vitro, refractory to viral reactivation. A Tat-inhibitor treatment combined with ART would be aimed at reducing the size of the latent reservoir pool by blocking ongoing viral replication, reactivation and replenishment of the latent viral reservoir, a key limitation of currnt ART. Here we propose to test dCA in rhesus macaques infected with simian immunodeficiency virus (SIV). We hypothesize that by reducing persistent, low-level virus production from reservoirs, dCA will i) reduce the size of the viral reservoir by preventing its continued replenishment, ii) prevent or at least significantly delay viral rebound upon ART discontinuation, and iii) reduce morbidities associated with persistent levels of immune activation caused by low-levels of virus replication in subjects on suppressive ART. During the R21 project phase we will validate that dCA can be efficiently used to block SIV transcription in primary rhesus macaque CD4+ lymphocytes. Upon successful accomplishment of R21 milestones, we will initiate the R33 phase of the project, which is aimed at determining the impact of combining dCA with ART, and whether dCA may replace ART once virus is transcriptionally suppressed.