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.

抽象的潜伏感染细胞库持续存在于艾滋病毒感染者 (PLWH) 的各个解剖部位，尽管进行了抗逆转录病毒治疗（ART），但大多数病毒受到抑制的个体仍能得到有效的病毒学控制。 ART 中断后病毒迅速反弹，为治疗的发展提供了强有力的理由即使在 ART 抑制的 HIV 感染中，也会观察到慢性炎症和免疫激活，伴随有限的 CD4+T 细胞重建、粘膜免疫功能障碍、合并症和加速低级持续转录和病毒蛋白从整合池中滴流产生。原病毒被认为是造成这些情况的部分原因，例如休克疗法等艾滋病毒根除策略。迄今为止尚未成功，人们考虑追求功能性治愈或艾滋病毒缓解作为一种值得探索的替代方案，功能性治疗需要长期、持久地控制病毒表达。尽管存在可检测到的病毒，但缺乏治疗，防止疾病进展和传播我们的团队一直处于开发此类策略的最前沿，该策略被称为“块-”。这种方法的前提是转录抑制剂可以介导表观遗传。沉默原病毒表达，将病毒锁定在深度潜伏状态，从该状态重新激活非常困难我们已经使用小分子证明了这一原理。 Tat 的二脱氢皮质素 A (dCA) 抑制剂，HIV 转录扩增的关键调节因子。在 HIV 潜伏期人源化小鼠模型中，随着时间的推移，dCA 对 HIV 转录的抑制会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的病毒再激活重新激活剂（LRA）1-8。我们相信，总体而言，HIV 转录抑制剂有可能改变我们治疗 HIV 的方式 1 感染。在这里，我们建议研究将转录抑制剂 dCA 添加到 ART 中的潜力。 dCA 不仅是一种抑制 SHIV 感染的恒河猴 (RhM) 模型的新分子。尚未进行临床探索的病毒靶标的活性，但这也为探索新的病毒靶标开辟了可能性在此我们建议：1）确定 dCA 在 ART 中的安全性和药代动力学。 RhMs；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；3) 研究 dCA 作为一线治疗对已建立的病毒库的大小。