Tyrosine kinase inhibition to block HIV-1 persistence: a pilot study

抑制酪氨酸激酶以阻止 HIV-1 持续存在：一项试点研究

基本信息

批准号：
10085120
负责人：
Adam Mitchell Spivak
金额：
$ 22.88万
依托单位：
UNIVERSITY OF UTAH
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-08-19 至 2023-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10085120
关键词：
Address Age Aging Antigens Biological Markers Biology of Aging Budgets CD4 Positive T Lymphocytes Cardiovascular Diseases Case Report Form Cell Aging Cell Proliferation Cells Chronic Chronic Disease Chronic Myeloid Leukemia Chronology Clinical Clinical Protocols Clinical Trials Dasatinib Data Development Disease Drug Targeting Drug usage FDA approved Frequencies Goals HIV-1 Immune Immune system Immunotherapy Individual Infection Inflammation Informed Consent Knowledge Life Longevity Manuals Measures Memory Metabolic syndrome Monitor Opportunistic Infections Outcome Pamphlets Participant Patients Pharmaceutical Preparations Pharmacology Physiological Pilot Projects Population Property Protein Tyrosine Kinase Proviruses Research Research Design Research Personnel Resources Rest Risk Role Safety Stable Populations Statistical Data Interpretation Systemic infection T-Lymphocyte Testing Therapeutic Training Tyrosine Kinase Inhibitor United States Viral Viremia Virus Latency age effect age related antiproliferative agents antiretroviral therapy cardiovascular disorder risk cardiovascular risk factor clinically relevant data management disorder risk exhaustion experience fitness frailty high risk idiopathic pulmonary fibrosis immune activation immunomodulatory strategy immunosenescence in vivo latent HIV reservoir macrophage memory CD4 T lymphocyte operation patient population pilot trial safety testing senescence success targeted treatment therapeutic target

项目摘要

PROJECT SUMMARY Despite the success of antiretroviral therapy (ART), people living with HIV-1 require life-long treatment due to viral persistence in long-lived cellular reservoirs, and experience a chronic state of immune activation and exhaustion that significantly contributes to the risk of cardiovascular disease and other life-threatening complications. The inability to address these clinically relevant shortcomings of ART represents a critical knowledge gap in the management of HIV-1 infection. Intensive efforts to perturb the latent reservoir via pharmacologic latency reversal or immune-based therapies targeting latently infected cells have not produced positive results to date. Similarly, attempts to directly address the chronic immune activation observed in chronic, treated HIV-1 infection have shown modest returns. The reservoir persists through cellular proliferation, though little effort has been made to evaluate the role of anti-proliferatives in reducing reservoir size. We and others have demonstrated the anti-proliferative and anti-HIV-1 effects of the FDA-approved drug and tyrosine kinase inhibitor dasatinib. While dasatinib has never been trialed for this indication, it was recently shown in a pilot clinical trial to act as a ‘senolytic,’ or a drug that can target cells responsible for the chronic inflammation associated with aging and aging-related conditions. The overall aim of this proposal is to plan a pilot clinical trial administering dasatinib to individuals living with treated HIV-1 infection to evaluate its ability to reduce the size of the HIV-1 reservoir and ameliorate the chronic immune activation that contributes to CVD risk in this population. The importance of developing strategies to address HIV-1 persistence, immunosenescence and serious pathophysiologic consequences including cardiovascular disease in treated HIV-1 infection are underscored by the chronologic aging of the HIV-1 infected population in the United States. The proposed pilot trial testing the anti-proliferative and senolytic properties of dasatinib in treated HIV-1 infection will have therapeutic implications for HIV-1 infection and a multitude of aging-related disease states including CVD.

项目概要尽管抗逆转录病毒疗法 (ART) 取得了成功，但 HIV-1 感染者仍需要终生治疗，因为病毒在长寿命细胞储存库中持续存在，并经历慢性免疫激活状态疲劳会显着增加患心血管疾病和其他危及生命的疾病的风险无法解决 ART 的这些临床相关缺点是一个关键问题。 HIV-1 感染管理方面的知识差距。针对潜伏感染细胞的药理学潜伏期逆转或基于免疫的疗法尚未产生同样，迄今为止也取得了积极的结果，试图直接解决观察到的慢性免疫激活问题。慢性、经过治疗的 HIV-1 感染已显示出适度的回归，并通过细胞持续存在。扩散，尽管很少有人努力评估抗增殖剂在减少储存库中的作用我们和其他人已经证明了 FDA 批准的药物的抗增殖和抗 HIV-1 作用。和酪氨酸激酶抑制剂达沙替尼虽然从未针对该适应症进行过试验，但最近进行了试验。一项试点临床试验显示，它可以作为一种“senolytic”，或者一种可以靶向导致慢性疾病的细胞的药物。该提案的总体目标是规划一个与衰老和衰老相关疾病相关的炎症。对 HIV-1 感染者进行达沙替尼治疗的试点临床试验，以评估其治疗能力减少 HIV-1 储存库的大小并改善导致 CVD 的慢性免疫激活制定应对 HIV-1 持续存在的策略的重要性，免疫衰老和严重的病理生理后果，包括接受治疗的心血管疾病美国 HIV-1 感染人群的年龄老化凸显了 HIV-1 感染。拟议的试点试验测试了达沙替尼在治疗的 HIV-1 中的抗增殖和衰老特性感染将对 HIV-1 感染和多种与衰老相关的疾病状态产生治疗意义包括CVD。