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: 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
• 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

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 潜伏感染细胞的储库持续存在于艾滋病毒感染者（PLWH）的各种解剖部位， 尽管通过抗逆转录病毒疗法（ART）进行了有效的病毒学控制。大多数病毒抑制个体 在ART中断后经历快速病毒反弹，为治愈的发展提供了强有力的理论基础 战略布局即使在ART抑制的HIV感染中，也观察到慢性炎症和免疫激活， 沿着有限的CD 4 +T细胞重建、粘膜免疫功能障碍、共病和加速的 老化从整合的DNA库中低水平持续转录和滴状产生病毒蛋白 前病毒被认为是造成这些病症的部分原因。艾滋病毒根除战略，如休克- 到目前为止，and-kill还没有成功，人们一直认为， 作为一个值得探索的替代方案。功能性治疗需要长期、持久地控制病毒在细胞中的表达， 缺乏治疗，阻止疾病进展和传播，尽管存在可检测的 整合前病毒。我们的团队一直处于开发此类战略的最前沿，称为块- 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 沉默前病毒的表达，锁定病毒在一个深刻的潜伏状态，从重新激活是非常重要的。 不太可能在ART停药后发生。我们已经证明了这一原则使用的小分子 达特的二脱氢皮质抑素A（dCA）抑制剂，是HIV转录扩增的关键调节因子。在体外和 在HIV潜伏期的人源化小鼠模型中，dCA随时间推移对HIV转录的抑制驱动病毒启动子 进入深度转录抑制，在治疗中断或潜伏时限制病毒再激活 再活化剂（LRA）1-8。 我们相信，艾滋病毒转录抑制剂，一般来说，有潜力改变我们治疗艾滋病毒的方式， 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。 方案在SHIV感染的恒河猴（RhM）模型中。dCA不仅是一种新的分子， 病毒靶点的活性尚未在临床上探索，但它也为探索新的 采取措施抗击艾滋病毒。在此，我们提出：1）确定dCA在ART中的安全性和药代动力学- 2）了解dCA治疗与组织中病毒RNA减少之间的关系， 治疗中断后至病毒反弹的时间;和3）研究dCA作为一线治疗对 已建立的病毒库的大小。