Clonal Hematopoeisis in HIV and Aging

项目摘要 数据支持患有糖尿病的人有更高的共病患病率，并加剧或加速衰老 艾滋病毒(PLWH)，包括较高的虚弱和身体残疾患病率。克隆的潜在作用 造血(CH)--具有获得性突变的造血干细胞的增殖。 竞争增长优势--在促进PLWH炎症和衰老相关并发症方面 未知。而CH在一般人群中的患病率随着年龄的增长而增加，是一种潜在的先兆 恶性、促炎状态与心血管疾病和死亡率相关，在以下方面存在重大差距 我们对慢性丙型肝炎的患病率和影响的了解与未感染艾滋病毒的对照组相比。在一只老鼠身上 模型中，细菌通过受损的上皮紧密连接穿过肠道屏障 胃肠道通过Toll样受体依赖引起内毒素反应性的CH克隆扩张 小路。在慢性HIV感染中，类似的肠道完整性受损状态可能有利于 CH克隆的扩展/持久性。我们的主要假设是CH在PLWH中更普遍， 会加剧/加速衰老。我们将使用多学科方法进行相关研究。 在人类身上实现以下目标：1)检测PLWH中CH的患病率和数量 与没有感染艾滋病毒的对照组相比；2)测试认知障碍、虚弱、体力减退 功能，以及在CH.我们将使用数据和存档的标本 来自多中心艾滋病中心的500名55岁及以上的艾滋病毒携带者和同等数量的非艾滋病毒携带者 队列研究--妇女机构间艾滋病毒研究结合队列研究。没有艾滋病毒的对照将被匹配 在年龄、种族和民族方面。我们将使用定向外显子组测序来检测血液中的CH突变 &gt；2%的变异等位基因分数作为CH检测的阈值，与我们之前在普通人群中的研究一样。我们 将测量炎症(白介素6)、肠道完整性和细菌的循环生物标记物 从存档的血浆样本中移位。我们新颖的探索性调查将产生重要的数据 为了设计更明确的人体研究，旨在了解衰老的发病机制-- PLWH的相关并发症，并将使未来的介入研究成为可能。

Project Summary Data support a higher prevalence of co-morbidities and accentuated or accelerated aging in people living with HIV (PLWH), including a higher prevalence of frailty and physical disability. The potential role of clonal hematopoiesis (CH) --the proliferation of hematopoetic stem cells with acquired mutations that confer a competitive growth advantage-- in promoting inflammation and aging-related complications in PLWH is unknown. While the prevalence of CH in the general population increases with age and is a potential pre- malignant, pro-inflammatory state associated with cardiovascular disease and mortality, there is a major gap in our knowledge about the prevalence and impact of CH in PLWH compared to controls without HIV. In a mouse model, bacterial translocation across the gut barrier via compromised epithelial tight junctions of the gastrointestinal tract causes endotoxin-responsive expansion of CH clones via toll-like receptor dependent pathways. An analogous state of compromised intestinal integrity in chronic HIV infection may favor expansion/persistence of CH clones. Our overarching hypothesis is that CH is more prevalent in PLWH and contributes to accentuated/accelerated aging. We will use a multidisciplinary approach with correlative studies in humans to address the following aims: 1) Test for the elevated prevalence and quantity of CH in PLWH compared to matched controls without HIV; 2) Test for increased cognitive impairment, frailty, reduced physical function, and inflammaging biomarkers in the presence of CH. We will use data and archived specimens from 500 participants age 55 and older living with HIV and an equal number without HIV from the Multicenter AIDS Cohort Study-Women's Interagency HIV Study Combined Cohort Study. Controls without HIV will be matched on age, race, and ethnicity. We will use targeted exome sequencing to detect CH mutations in blood using >2% variant allele fraction as the threshold for CH detection as in our prior study in the general population. We will measure a circulating biomarker of inflammation (interleukin-6), intestinal integrity, and bacterial translocation from archived plasma specimens. Our novel, exploratory investigations will yield important data to inform the design of more definitive human studies aimed at understanding the pathogenesis of aging- related complications in PLWH and will enable future interventional studies.