Modulating Immune Senescence of Effector Lymphocytes in Chronic HIV Infection

项目摘要/摘要 联合抗逆转录病毒疗法(ART)已经将HIV-1感染从一种无法治疗的、致命的 变成了一个可控制的医疗问题。然而，免疫系统并没有完全恢复健康。 尽管抗逆转录病毒治疗恢复了CD4+T细胞亚群，并持久地抑制了病毒血症。免疫 慢性抗逆转录病毒治疗中HIV-1感染者的效应细胞(CD8+T细胞和NK细胞)表现为 免疫衰竭的表型。经治疗的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)。持续性免疫异常伴随着临床 对发病率和死亡率增加的观察使人们认识到，治疗艾滋病毒-1类似于一种状态 加速的免疫老化。这有多个潜在的原因，包括免疫程度 治疗前HIV-1感染引起的调节失调，尽管病毒在细胞内持续存在 艺术，以及无限期的艺术管理本身。了解这些因素的相对贡献将是 对于改善日益增长的老年HIV-1阳性患者的预后至关重要。 雷帕霉素(MTOR)的作用靶点是天然免疫细胞和获得性免疫细胞中的一种活性蛋白。 它控制着细胞的新陈代谢、生长和生存。而mTOR抑制剂雷帕霉素是FDA批准的 并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有 已被证明具有免疫刺激作用，增强抗病原体和抗肿瘤反应。此外， 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，提示mTOR信号可能在调节 病毒持久力。这些证据表明，mTOR信号是一个高产量的目标，可以改善 慢性、经治疗的HIV-1感染的免疫功能障碍。 这项应用提出了调节抗病毒功能和血管周围炎症的实验 效应淋巴细胞通过mTOR抑制而诱导。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 接受抗逆转录病毒治疗的HIV-1感染患者的慢性免疫激活和免疫衰老的形式。这个 了解免疫衰老和严重病理生理机制的重要性 时间顺序强调了治疗HIV-1感染的后果，包括心血管疾病 美国HIV-1感染人口的老龄化。我们提出了假设驱动的实验 为评价mTOR抑制对循环CD8+T细胞免疫表型和功能的影响 以及经治疗的HIV-1感染者外周血中的NK细胞亚群。探索 经治疗的HIV-1感染的免疫衰老将对HIV-1感染和 包括心血管疾病在内的多种与衰老相关的疾病状态。

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.