Evaluation of didehydro-Cortistatin A as a block-and-lock agent for a functional HIV cure in a macaque model

双脱氢皮质抑素 A 作为阻断剂在猕猴模型中功能性 HIV 治愈的评价

• 批准号: 10591883
• 负责人: David T Evans
• 金额: $ 45.09万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-20 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10591883
• 关键词: Evaluation; didehydro; Cortistatin; block; lock

Abstract A reservoir of latently infected cells persists in various anatomical sites in people living with HIV (PLWH), despite effective virological control by antiretroviral therapy (ART). The majority of virally suppressed individuals experience rapid viral rebound upon ART interruption, providing a strong rationale for the development of cure strategies. Even in an ART-suppressed HIV infection, chronic inflammation and immune activation are observed, along with limited CD4+T cell reconstitution, mucosal immune dysfunction, co-morbidities, and accelerated ageing. Low-grade persistent transcription and trickling production of viral proteins from the pool of integrated proviruses are believed to be partly responsible for these conditions. HIV eradication strategies such as shock- and-kill have not been successful so far, and the pursuit of a functional cure or HIV remission has been thought as an alternative worth exploring. A functional cure entails long-term, durable control of viral expression in the absence of therapy, preventing disease progression and transmission, despite the presence of detectable integrated proviruses. Our group has been at the forefront of developing one such strategy, labeled the block- and-lock approach. The premise of this approach is that transcriptional inhibitors can mediate epigenetic silencing of proviral expression, locking the virus in a profound state of latency from which reactivation is very unlikely to occur upon ART discontinuation. We have demonstrated this principle using the small molecule didehydro-Cortistatin A (dCA) inhibitor of Tat, the key regulator of HIV transcriptional amplification. In in vitro and in humanized mouse models of HIV latency, dCA inhibition of HIV transcription over time drives the viral promoter into deep transcriptional inhibition, limiting viral reactivation upon treatment interruption or with latency reactivating agents (LRAs)1–8. We believe that HIV transcriptional inhibitors, in general, have the potential to transform the way we treat HIV- 1 infections. Here we propose to investigate the potential of adding the transcriptional inhibitor dCA to an ART regimen in the rhesus macaque (RhM) model of SHIV infection. Not only is dCA a new molecule that inhibits the activity of a viral target not yet clinically explored, but it also opens the possibility for exploration of novel approaches to fight HIV. Here we propose to: 1) determine the safety and pharmacokinetics of dCA in ART- treated RhMs; 2) understand the relationship between dCA treatment and reduction in viral RNA in tissues, with the time to viral rebound upon treatment interruption; and 3) study the impact of dCA as front-line therapy on the size of the established viral reservoir.

摘要 潜伏感染细胞的储存库持续存在于艾滋病毒携带者(PLWH)的不同解剖部位， 尽管通过抗逆转录病毒疗法(ART)有效地控制了病毒学。大多数被病毒抑制的个体 经历ART中断后病毒迅速反弹，为治疗的发展提供了强有力的理论基础 战略。即使在ART抑制的HIV感染中，也可以观察到慢性炎症和免疫激活， 伴随着有限的CD4+T细胞重建，粘膜免疫功能障碍，共病，并加速 老龄化。从整合池中低级持续转录和滴流生产病毒蛋白 前病毒被认为是造成这些情况的部分原因。根除艾滋病毒的战略，如休克- 到目前为止，AND-KILE还没有成功，人们一直在寻找有效的治疗方法或缓解艾滋病毒的方法 作为一种值得探索的替代方案。功能性治疗需要长期、持久地控制病毒在 缺乏治疗，防止疾病进展和传播，尽管存在可检测到的 整合的前病毒。我们的团队一直站在开发这样一种战略的前沿，被称为区块- 并锁定进场。这种方法的前提是转录抑制物可以介导表观遗传学。 沉默前病毒的表达，将病毒锁定在一种深刻的潜伏期状态，从这种状态开始重新激活 不太可能在艺术中断时发生。我们已经用小分子证明了这一原理 二氢皮质抑素A(DCA)TAT的抑制剂，HIV转录扩增的关键调节因子。在体外和 在HIV潜伏的人源化小鼠模型中，随着时间的推移，DCA抑制HIV转录驱动病毒启动子 进入深度转录抑制，在治疗中断或潜伏时限制病毒重新激活 复活剂(LRA)1-8。 我们相信，总的来说，艾滋病毒转录抑制物有可能改变我们治疗艾滋病毒的方式-- 感染1例。在这里，我们建议研究在ART中添加转录抑制物DCA的可能性 新城疫病毒感染恒河猴(RHM)模型中的治疗方案。DCA不仅是一种新的分子，可以抑制 一个尚未临床探索的病毒靶点的活性，但它也为探索新的 抗击艾滋病毒的方法。在此，我们建议：1)在ART中测定DCA的安全性和药代动力学。 治疗的REM；2)了解DCA治疗与组织中病毒RNA减少之间的关系， 治疗中断后病毒反弹的时间；以及3)研究DCA作为一线治疗对 已建立的病毒库的大小。