Clonal Hematopoeisis in HIV and Aging

项目摘要 数据支持患有糖尿病的人群中合并症的患病率较高，并且衰老加重或加速。 艾滋病毒携带者（艾滋病毒/艾滋病感染者），包括虚弱和身体残疾的发病率较高。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，赋予 竞争性生长优势-在促进炎症和衰老相关的并发症在PLWH是 未知虽然CH在一般人群中的患病率随着年龄的增长而增加，并且是一个潜在的前 与心血管疾病和死亡率相关的恶性、促炎状态， 与无艾滋病毒的对照组相比，我们对艾滋病毒感染者中CH的患病率和影响的了解。在小鼠 模型，细菌易位通过受损的上皮细胞紧密连接穿过肠道屏障， 胃肠道通过Toll样受体依赖性引起CH克隆的内毒素应答性扩增 途径。慢性HIV感染者肠道完整性受损的类似状态可能有利于 CH克隆的扩增/持久性。我们的总体假设是CH在PLWH中更普遍， 有助于加重/加速老化。我们将采用多学科方法进行相关研究 在人类中，以解决以下目标：1）测试PLWH中CH的患病率和数量增加 与没有HIV的匹配对照相比; 2）测试认知障碍、虚弱、身体机能降低、 功能和炎症生物标志物在CH的存在。我们将使用数据和存档标本， 500名年龄在55岁及以上的艾滋病毒感染者和同等数量的非艾滋病毒感染者参加了多中心艾滋病 队列研究-妇女机构间艾滋病毒研究联合队列研究。不含HIV的对照将匹配 年龄，种族，民族我们将使用靶向外显子组测序来检测血液中的CH突变， >2%的变异等位基因分数作为CH检测的阈值，如我们在一般人群中的先前研究中那样。我们 将测量炎症（白细胞介素-6），肠道完整性和细菌的循环生物标志物， 来自存档血浆标本的易位。我们新颖的探索性调查将产生重要的数据 为设计更明确的人类研究提供信息，旨在了解衰老的发病机制- PLWH的相关并发症，并将使未来的干预研究。

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.