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

项目总结/摘要 在有效的抗逆转录病毒疗法的帮助下，艾滋病毒感染者的预期寿命显著提高，但 有注射吸毒史的艾滋病毒感染者的存活率仍然明显不足。差距 在PWID中，部分归因于疾病谱向衰老相关疾病的转变 虚弱是一种重要的与衰老相关的脆弱状态， 压力，随着HIV感染负担的增加，与炎症的加剧密切相关， 预测PWID中的过早死亡率和年龄相关发病率。注射毒品本身会增加 HIV感染的严重程度人类肠道微生物生态系统（肠道微生物组） 炎症和免疫。肠道微生物组的改变（肠道生态失调）以及相关的 肠道结构和免疫完整性的破坏构成炎症-微生物组特征（肠道 生态失调，肠道通透性增加，微生物产物易位，免疫激活， 炎症）与不利的衰老相关的炎症状况和疾病有关。提出了一种 系统研究HIV感染和注射毒品使用（IDU）在定义炎症性疾病中的作用， 微生物组特征和确定该特征与虚弱的关系。通过评估 艾滋病静脉注射经验（ALIVE）队列中的粪便和粘膜微生物组- 感染和流行病学可比的艾滋病毒未感染的PWID，我们将确定如何艾滋病毒感染和 活动性IDU改变微生物组组成和功能以及这些变化与炎症的关系 和虚弱的进展。使用无菌小鼠模型，我们将进一步定义虚弱的人类 微生物群落和基因产物会导致炎症。这些研究将有助于阐明 在HIV感染的PWID中，肠道微生物决定因素的脆弱性，并可以显着告知微生物群 调节策略，以减少ART以外的虚弱相关炎症。了解肠道的作用 微生物组与艾滋病毒，注射毒品使用和脆弱性的关系仍然是减少显着的 HIV感染者PWID的临床结局差异。

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.