TGFBR1 Blockade as Novel Release and Kill HIV Strategy

TGFBR1 阻断作为新的释放和杀死 HIV 策略

• 批准号: 10358122
• 负责人: Elena Martinelli
• 金额: $ 78.67万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-01 至 2023-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10358122
• 关键词: Adherence; Automobile Driving; Bar Codes; Biological Assay; Blood; Cells; Cessation of life; Chronic Disease; Clinic; Combined Modality Therapy; Control Groups; Data; Development; Disease; Disease Progression; Epidemic; Flow Cytometry; HIV; Human immunodeficiency virus test; Immune; Immune System Diseases; Immune response; Immunity; Immunologic Suppressor Factors; Immunosuppression; In Vitro; Individual; Infusion procedures; Interruption; Intervention; Lead; Left; Macaca; Macaca mulatta; Maintenance; Malignant Neoplasms; Mediating; Molecular; Morbidity - disease rate; PET/CT scan; Patients; Pharmaceutical Preparations; Pilot Projects; Play; Property; Regimen; Role; SIV; Shock; Signal Transduction; Site; Specificity; T-Cell Proliferation; T-Lymphocyte; TGFBR1 gene; Techniques; Testing; Therapeutic; Tissues; Toxic effect; Transforming Growth Factor alpha; Transforming Growth Factor beta; Treatment Protocols; Viral; Virus; X-Ray Computed Tomography; antiretroviral therapy; base; cancer therapy; clinical development; clinical investigation; clinically relevant; cost; in vitro Model; in vivo; inhibitor/antagonist; innovation; neutralizing antibody; novel; novel therapeutic intervention; pharmacokinetics and pharmacodynamics; pre-clinical; purge; reactivation from latency; receptor; research clinical testing; response; therapeutic evaluation; tool; treatment duration; viral rebound; virology

ABSTRACT For many HIV infected people, lifelong combination antiretroviral therapy (cART) has converted the HIV epidemic from death sentence into a manageable chronic disease. However, the HIV reservoir persists in all treated individuals and viral rebound occurs upon cART interruption in the vast majority of patients. Given the challenges related to lifelong cART treatment such as adherence, viral escape, toxicity, and costs, finding novel ways to eradicate the virus and/or induce sustained virologic control in absence of cART is a very high priority in the HIV field. Tissues are major sites for HIV latency and notable contributors to viral rebound after cART interruption. TGF-β is an important immune suppressor factor, which orchestrates tissue immunity. Levels of TGF-β remain elevated in HIV infected individuals even after years of fully suppressive cART and contribute to immune suppression as well as to the development of non-AIDS-related, non-communicable disorders via pro-fibrotic mechanisms. TGF-β1 inhibits TCR-driven T cell proliferation and the maturation and function of other immune cell subsets. Importantly, TGF-β is currently being used to induce HIV latency in in vitro models of HIV latency in primary T cells. Our preliminary data demonstrate that blocking TGF-β signaling in vivo favors HIV latency reversal especially in tissues. Herein, we propose to test a novel latency reversal and immune stimulatory strategy based on the activity of a specific inhibitor of the TGF-β type I receptor (TGFBR1) in rhesus macaques. This strategy has given promising results in a pilot study in macaques and we propose to evaluate the effect of a prolonged administration similar to the regimen currently employed for cancer therapy. Moreover, we propose to determine the mechanism of action of the TGFBR1 inhibitor in vivo to better clarify its utility in the development of novel HIV cure strategies. Finally, we hypothesize that anti-HIV broadly neutralizing antibodies (bNAbs) may synergize with the TGFBR1 inhibitor in reducing the HIV reservoir and stimulate HIV-specific immune responses. Thus, we plan to perform a proof-of-concept study to determine the efficacy of combining the TGFBR1 inhibitor with bNAbs against SIV in SIV infected, cART treated rhesus macaques in reducing SIV reservoir and leading to virologic control after cART interruption. In summary, we propose the pre-clinical investigation of a novel TGFBR1 inhibitor that has the potential to be a powerful new addition to the toolbox of “shock and kill” HIV curative strategies.

摘要 对于许多艾滋病毒感染者来说，终身联合抗逆转录病毒治疗（cART）已经改变了艾滋病毒的流行 从死刑变成了一种可以控制的慢性病然而，在所有接受治疗的人中， 在大多数患者中，在cART中断时发生病毒反弹。鉴于挑战 与终身cART治疗相关的问题，如依从性、病毒逃逸、毒性和成本，寻找新的方法， 在没有cART的情况下，根除病毒和/或诱导持续的病毒学控制是HIV治疗中非常高的优先级。 领域组织是HIV潜伏期的主要部位，也是cART中断后病毒反弹的显著原因。 TGF-β是一种重要的免疫抑制因子，负责协调组织免疫。TGF-β水平保持不变 即使在多年的完全抑制性cART后，HIV感染者的抗体水平也会升高， 抑制以及通过促纤维化发展非艾滋病相关的非传染性疾病 机制等TGF-β1抑制TCR驱动的T细胞增殖以及其他免疫调节因子的成熟和功能。 细胞亚群重要的是，TGF-β目前被用于在体外HIV潜伏模型中诱导HIV潜伏 在原代T细胞中。我们的初步数据表明，在体内阻断TGF-β信号有利于HIV潜伏期 逆转，尤其是在组织中。在此，我们建议测试一种新的潜伏期逆转和免疫刺激， 基于恒河猴中TGF-β I型受体（TGFBR 1）的特异性抑制剂的活性的策略。 这种策略在猕猴的初步研究中取得了可喜的结果，我们建议评估 类似于目前用于癌症治疗的方案的延长给药。此外，我们建议 确定TGFBR 1抑制剂的体内作用机制，以更好地阐明其在开发中的效用 新型艾滋病治疗策略。最后，我们假设抗HIV广泛中和抗体（bNAbs）可能 与TGFBR 1抑制剂协同减少HIV储库并刺激HIV特异性免疫应答。 因此，我们计划进行一项概念验证研究，以确定TGFBR 1抑制剂联合 在SIV感染的恒河猴中，用抗SIV的bNAbs，cART治疗减少了SIV储库， cART中断后的病毒学控制。总之，我们提出了一种新的临床前研究 TGFBR 1抑制剂有可能成为“休克和杀死”艾滋病毒工具箱中强大的新成员 治疗策略。