Modulating Immune Senescence of Effector Lymphocytes in Chronic HIV Infection

调节慢性 HIV 感染中效应淋巴细胞的免疫衰老

基本信息

批准号：
9811781
负责人：
Adam Mitchell Spivak
金额：
$ 11.44万
依托单位：
UNIVERSITY OF UTAH
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-08-15 至 2021-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9811781
关键词：
Age Aging Anti-Retroviral Agents Antitumor Response Antiviral Agents Autologous Blood Vessels CD4 Positive T Lymphocytes CD8-Positive T-Lymphocytes CD8B1 gene Cardiovascular Diseases Cell Compartmentation Cell physiology Cell surface Cells Chronic Chronology Clinical Coculture Techniques Color Disease Dose Effector Cell Engraftment Epidemic Etiology Evaluation Exposure to FDA approved FRAP1 gene Flow Cytometry Functional disorder Generations Goals Growth HIV Infections HIV Seropositivity HIV-1 Immune Immune System Diseases Immune system Immunologics Immunomodulators Immunophenotyping Immunosuppression In Vitro Individual Infection Infiltration Inflammation Inflammatory Kidney Transplantation Knowledge Longevity Lymphocyte Measures Medical Metabolism Morbidity - disease rate Mus Natural Killer Cells Organ Transplantation Outcome Measure Participant Pathway interactions Patients Pharmaceutical Preparations Phenotype Phosphotransferases Population Predisposition Prevalence Reactive Oxygen Species Research Proposals Rest Risk Role Signal Transduction Sirolimus T-Lymphocyte Therapeutic Transplant Recipients Treatment outcome United States Vascular Diseases Viral Viral Physiology Viremia Virus Virus Replication age effect age related antiretroviral therapy cardiovascular disorder risk cytokine exhaustion experimental study fitness frailty humanized mouse immune activation immunosenescence improved improved outcome inhibitor/antagonist memory CD4 T lymphocyte mortality mouse model pathogen peripheral blood restoration senescence success

项目摘要

PROJECT SUMMARY / ABSTRACT Combination antiretroviral therapy (ART) has transformed HIV-1 infection from an untreatable, lethal condition into a manageable medical problem. However, the immune system does not return to full fitness despite the restoration of the CD4+ T cell compartment and durable suppression of viremia by ART. Immune effector cells (CD8+ T cells and NK cells) of HIV-1-infected individuals on chronic ART demonstrate a phenotype of immune exhaustion. Treated HIV-1 infection is associated with significant risk of age-related diseases, including cardiovascular disease (CVD). Persistent immunological abnormalities paired with clinical observations of increased morbidity and mortality have led to recognition that treated HIV-1 resembles a state of accelerated immunological aging. This has multiple potential causes, including the degree of immune dysregulation caused by HIV-1 infection prior to treatment, the persistence of virus in cellular reservoirs despite ART, and indefinite ART administration itself. Understanding the relative contribution of these factors will be critical to improve outcomes for the growing population of aging HIV-1-positive patients. The mechanistic target of rapamycin (mTOR) is a kinase active in innate and adaptive immune cells that governs cellular metabolism, growth and survival. While the mTOR inhibitor rapamycin is FDA-approved and widely used for chronic immune suppression in organ transplant recipients, this drug at lower dosing has been shown to be immune-stimulatory, boosting both anti-pathogen and anti-tumor responses. Furthermore, HIV-1-positive kidney transplant recipients treated with rapamycin were found to have smaller HIV-1 reservoirs than those taking other immunomodulatory agents, suggesting a possible role of mTOR signaling in regulating viral persistence. These lines of evidence identify mTOR signaling as a high yield target to ameliorate the immunologic dysfunction of chronic, treated HIV-1 infection. This application proposes experiments to modulate the anti-viral function and perivascular inflammation induced by effector lymphocytes through mTOR inhibition. Despite the suppression of viral replication by ART and consequent improvement in mortality, it has become clear that immunologic dysregulation persists in the form of chronic immune activation and immunologic aging in HIV-1-infected ART-treated patients. The importance of understanding the mechanisms leading to immunosenescence and serious pathophysiologic consequences including cardiovascular disease in treated HIV-1 infection is underscored by the chronologic aging of the HIV-1 infected population in the United States. We propose hypothesis-driven experiments in order to evaluate the role of mTOR inhibition on the immunophenotype and function of circulating CD8+ T cells and NK cell subsets in the peripheral blood of treated HIV-1 infected individuals. Exploring the drivers of immunosenescence 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/摘要联合抗逆转录病毒疗法 (ART) 已将 HIV-1 感染从无法治愈的致命疾病转变为将病情转化为可控制的医疗问题。然而，免疫系统并没有完全恢复健康尽管 ART 恢复了 CD4+ T 细胞区室并持久抑制了病毒血症。免疫长期 ART 中 HIV-1 感染者的效应细胞（CD8+ T 细胞和 NK 细胞）表现出免疫耗竭的表型。接受治疗的 HIV-1 感染与年龄相关的重大风险相关疾病，包括心血管疾病（CVD）。持续的免疫学异常与临床对发病率和死亡率增加的观察使人们认识到接受治疗的 HIV-1 类似于一种状态加速免疫老化。这有多种潜在原因，包括免疫程度治疗前 HIV-1 感染引起的失调，尽管病毒在细胞储存库中持续存在 ART 以及无限期的 ART 给药本身。了解这些因素的相对贡献将有助于对于改善不断增长的老年 HIV-1 阳性患者的治疗结果至关重要。雷帕霉素 (mTOR) 的机制靶点是一种在先天性和适应性免疫细胞中活跃的激酶控制细胞的新陈代谢、生长和生存。 mTOR 抑制剂雷帕霉素已获得 FDA 批准这种药物在较低剂量下广泛用于器官移植受者的慢性免疫抑制已被证明具有免疫刺激作用，可增强抗病原体和抗肿瘤反应。此外，研究发现，接受雷帕霉素治疗的 HIV-1 阳性肾移植受者的 HIV-1 储存库较小与服用其他免疫调节剂的患者相比，这表明 mTOR 信号传导在调节中可能发挥作用病毒的持续存在。这些证据表明 mTOR 信号传导是改善慢性、已治疗的 HIV-1 感染的免疫功能障碍。该申请提出了调节抗病毒功能和血管周围炎症的实验由效应淋巴细胞通过 mTOR 抑制诱导。尽管ART抑制了病毒复制以及随之而来的死亡率的改善，很明显，免疫失调在人群中持续存在 HIV-1感染的ART治疗患者中慢性免疫激活和免疫老化的形式。这了解导致免疫衰老和严重病理生理学机制的重要性按时间顺序强调了接受治疗的 HIV-1 感染中包括心血管疾病在内的后果美国 HIV-1 感染人口的老龄化。我们提出假设驱动的实验为了评估 mTOR 抑制对循环 CD8+ T 细胞的免疫表型和功能的作用以及接受治疗的 HIV-1 感染者外周血中的 NK 细胞亚群。探索驱动因素治疗后的 HIV-1 感染中的免疫衰老将对 HIV-1 感染产生治疗意义，并且多种与衰老相关的疾病状态，包括心血管疾病。