Frailty, HIV Infection, Injection Drug Use and the Inflammatory-Microbiome

项目摘要/摘要 通过有效的抗逆转录病毒疗法(ART)，艾滋病毒感染者的预期寿命显著延长，但 有注射吸毒史的艾滋病毒感染者在存活率方面仍然存在明显不足。差距 在PWID中，部分归因于疾病谱向与衰老相关的条件的转变 由持续的炎症驱动，即使是在接受艺术治疗的情况下。虚弱是与衰老相关的一种重要状态，易受 压力，艾滋病毒感染的负担增加，与高度炎症密切相关，以及 PWID患者过早死亡和与衰老相关的发病率的预测。注射毒品本身会增加 艾滋病病毒感染的严重程度。人类肠道微生物生态系统(肠道微生物组)对 炎症和免疫力。肠道微生物群的改变(肠道生物失调)与相关的 肠道结构和免疫完整性的破坏构成了炎性微生物组特征(肠道 微生物失调，肠道通透性增加，微生物产物移位，免疫激活，增强 炎症)与与衰老相关的不良炎症条件和疾病有关。建议的是一个 系统研究艾滋病毒感染和注射吸毒(IDU)在确定炎性- 微生物组特征及其与脆性关系的测定。通过评估 艾滋病患者的粪便和粘膜微生物群与静脉注射经历(活的)HIV队列有关。 感染和流行病学具有可比性的未感染艾滋病毒的PWID，我们将确定艾滋病毒感染和 活性IDU改变微生物群组成和功能及其与炎症的关系 以及随着时间的推移而变得脆弱。使用无菌小鼠模型，我们将进一步定义虚弱的人类 促进炎症的微生物群落和基因产品。这些研究将有助于澄清 研究HIV感染的PWID患者肠道微生物脆弱的决定因素，并可显著告知微生物区系 调节策略，以减少ART以外的虚弱相关炎症。理解直觉的作用 与艾滋病毒、注射用药和脆弱有关的微生物组仍然是减少标记的下一步的关键 HIV感染的PWID患者的临床结果存在差异。

PROJECT SUMMARY/ABSTRACT With effective antiretroviral therapy (ART), life expectancy for HIV-infected persons has markedly improved, yet marked deficits in survival remain for HIV-infected persons with a history of injecting drugs (PWID). Disparities among PWID have been attributed in part to a shifting spectrum of disease to aging-associated conditions driven by persistent inflammation even with ART. Frailty is an important aging-related state of vulnerability to stress, with an increased burden in HIV infection, strongly associated with heightened inflammation, and predictive of premature mortality and aging-related morbidity among PWID. Injecting drugs itself can increase the severity of inflammation in HIV. The human gut microbial ecosystem (gut microbiome) critically regulates inflammation and immunity. Alterations in the gut microbiome (gut dysbiosis) together with associated disruptions of gut structure and immune integrity constitute an inflammatory-microbiome signature (gut dysbiosis, increased gut permeability, translocation of microbial products, immune activation, heightened inflammation) linked to adverse aging-associated inflammatory conditions and disease. Proposed is a systematic investigation of the role of HIV infection and injection drug use (IDU) in defining the inflammatory- microbiome signature and determination of the relationship of this signature to frailty. Through assessments of the fecal and mucosal microbiome in the AIDS Linked to the IntraVenous Experience (ALIVE) cohort of HIV- infected and epidemiologically comparable HIV-uninfected PWID, we will determine how HIV infection and active IDU alter microbiome composition and function and the relationship of these changes to inflammation and frailty progression over time. Using a germ free murine model, we will further define the frail human microbial communities and gene products that precipitate inflammation. These studies will facilitate elucidation of gut microbial determinants of frailty among HIV-infected PWID and could significantly inform microbiota modulation strategies to reduce frailty-associated inflammation beyond ART. Understanding the role of the gut microbiome in relation to HIV, injection drug use, and frailty remains a critical next step to reducing the marked disparities in clinical outcomes among HIV-infected PWID.