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

• 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
• 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

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.

项目摘要 尽管抗逆转录病毒疗法（ART）取得了成功，但HIV-1感染者需要终身治疗，因为 病毒在长寿细胞库中持续存在，并经历免疫激活的慢性状态， 疲劳，显着有助于心血管疾病和其他危及生命的风险 并发症无法解决ART的这些临床相关缺点代表了一个关键问题， 艾滋病毒感染管理方面的知识差距。加大力度扰动潜在储层， 针对潜伏感染细胞的药理学潜伏逆转或基于免疫的疗法尚未产生 迄今为止取得了积极成果。类似地，试图直接解决在免疫系统中观察到的慢性免疫激活。 慢性、经治疗的HIV-1感染显示出适度的回报。水库通过细胞持续存在， 增殖，尽管很少努力评估抗增殖剂在减少储库中的作用 尺寸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。虽然达沙替尼从未被用于这种适应症，但最近 在试点临床试验中显示，它可以作为一种“衰老清除剂”，或者一种可以靶向导致慢性衰老的细胞的药物。 炎症与衰老和衰老相关的条件。本提案的总体目标是规划一个 对接受治疗的HIV-1感染者进行达沙替尼给药的试点临床试验，以评估其 减少HIV-1储存库的大小，改善导致CVD的慢性免疫激活 这一人群的风险。必须制定战略，解决艾滋病毒-1持续存在的问题， 免疫衰老和严重的病理生理后果，包括心血管疾病， 在美国，HIV-1感染者的年龄老化突出了HIV-1感染。 拟议的试点试验测试达沙替尼在治疗的HIV-1中的抗增殖和衰老特性 感染将对HIV-1感染和许多与衰老有关的疾病状态产生治疗意义 包括CVD。