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

基本信息

批准号：
10403162
负责人：
David T Evans
金额：
$ 44.11万
依托单位：
SCRIPPS FLORIDA
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-20 至 2022-04-01
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10403162
关键词：
Acute Aging Anatomy Anti-Retroviral Agents Biological Assay Biopsy Blood CD4 Positive T Lymphocytes Cells Chemistry Chronic Clinic Clinical Colon Complete Blood Count DNA Development Disease Progression Disease remission Dose Drug Kinetics Drug or chemical Tissue Distribution Evaluation Genetic Transcription Goals HIV HIV Infections HIV-1 Hormones Immune System Diseases In Vitro Individual Infection Inflammation Injections Interruption Label Macaca Macaca mulatta Malignant Neoplasms Measurement Measures Mediating Modeling Monitor Mucous Membrane Peripheral Blood Mononuclear Cell Pharmaceutical Preparations Phase Plasma Production Proviruses RNA Recrudescences Regimen Residual state Resistance Rest SIV Safety Serum Shock T cell reconstitution T-Cell Depletion Time Tissues Toxic effect Variant Viral Viral Proteins Viral reservoir Viremia Virus Virus Replication acute infection antiretroviral therapy comorbidity cortistatin disease transmission epigenetic silencing experience experimental study fighting humanized mouse immune activation inflammatory marker inhibitor/antagonist insight lymph node biopsy memory CD4 T lymphocyte mouse model novel strategies particle prevent promoter simian human immunodeficiency virus small molecule subcutaneous transcriptome sequencing viral RNA viral rebound virology

项目摘要

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.

抽象的艾滋病毒（PLWH）的患者的各种解剖部位，一个潜在感染细胞的水库持续存在尽管通过抗逆转录病毒疗法有效控制病毒学控制（ART）。大多数病毒抑制的人在艺术中断时经历快速的病毒反弹，为治愈的开发提供了强有力的理由策略。即使在抑制ART抑制的HIV感染中，也观察到慢性感染和免疫激活，也会观察到以及有限的CD4+T细胞重建，粘膜免疫功能障碍，合并症和加速老化。从综合据信，对这些条件是部分责任。消除艾滋病毒策略，例如冲击 - 到目前为止，杀害还没有成功，并且已经认为对功能治愈或艾滋病毒缓解的追求作为值得探索的替代性。功能性治疗实体长期，持久的病毒表达控制缺乏治疗，预防疾病进展和传播，可检测到综合的预科病毒。我们的小组一直处于制定一种这样一种策略的最前沿，标记了块和锁方法。这种方法的前提是转录抑制剂可以介导表观遗传学对病毒表达的沉默，将病毒锁定在深度的潜伏状态下，重新激活非常停用艺术时不太可能发生。我们已经使用小分子证明了这一原理 Didehydro-Cortistatin A（DCA）抑制剂TAT是HIV转录扩增的关键调节剂。在体外和在艾滋病毒潜伏期的人性化小鼠模型中，DCA对HIV转录的抑制作用驱动病毒启动子进入深度转录抑制，限制治疗中断或潜伏期时的病毒重新激活重新激活剂（LRAS）1-8。我们认为，HIV转录抑制剂通常有可能改变我们对待HIV的方式 1个感染。在这里，我们建议研究将转录抑制剂DCA添加到ART的潜力 SHIV感染的恒河猴（RHM）模型中的方案。 DCA不仅是抑制的新分子病毒靶的活动尚未在临床上探索，但也为探索新颖的可能性开辟了可能性与艾滋病毒作斗争的方法。在这里我们建议：1）确定DCA在艺术中的安全性和药代动力学处理过的RHM； 2）了解DCA治疗与组织病毒RNA减少之间的关系，治疗中断时病毒反弹的时间； 3）研究DCA作为前线疗法对已建立的病毒效果师的大小。