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

• 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
• 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

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.

项目总结/摘要 联合抗逆转录病毒疗法（ART）已将HIV-1感染从一种无法治疗的致命疾病 将病情转化为可控的医疗问题。然而，免疫系统并没有完全恢复健康， 尽管ART恢复了CD 4 + T细胞区室并持久抑制了病毒血症。 接受慢性ART治疗的HIV-1感染者的效应细胞（CD 8 + T细胞和NK细胞）显示， 免疫衰竭的表型。接受治疗的HIV-1感染与年龄相关的显著风险相关 心血管疾病（CVD）。持续性免疫异常伴临床 对发病率和死亡率增加的观察使人们认识到，治疗HIV-1类似于一种状态， 免疫老化的加速。这有多种潜在的原因，包括免疫程度 在治疗前由HIV-1感染引起的调节失调，尽管病毒在细胞储库中持续存在， ART和无限期ART管理本身。了解这些因素的相对贡献将是 对于改善日益增长的老龄HIV-1阳性患者的结局至关重要。 雷帕霉素的机制靶点（mTOR）是一种在先天性和适应性免疫细胞中具有活性的激酶 控制着细胞的新陈代谢，生长和存活虽然mTOR抑制剂雷帕霉素是FDA批准的 广泛用于器官移植受者的慢性免疫抑制，这种药物在较低剂量下 已被证明是免疫刺激，增强抗病原体和抗肿瘤反应。此外，委员会认为， 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 比服用其他免疫调节剂的人，这表明mTOR信号在调节免疫调节中的可能作用。 病毒持久性这些证据将mTOR信号传导确定为改善免疫缺陷的高产靶标。 慢性HIV-1感染治疗后免疫功能障碍。 本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可以抑制病毒复制 以及随之而来的死亡率的改善，已经清楚的是，免疫失调持续存在于 HIV-1感染ART治疗患者的慢性免疫激活和免疫老化形式。的 理解导致免疫衰老和严重的病理生理学机制的重要性 结果包括心血管疾病治疗HIV-1感染是强调的时间顺序 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CD 8 + T细胞的免疫表型和功能的作用， 和NK细胞亚群。探索驱动因素 HIV-1感染治疗后的免疫衰老对HIV-1感染的治疗有意义， 许多与衰老相关的疾病状态，包括CVD。