Clonal Hematopoeisis in HIV and Aging

HIV 和衰老中的克隆造血

基本信息

批准号：
10013829
负责人：
MARSHALL J GLESBY
金额：
$ 21.19万
依托单位：
WEILL MEDICAL COLL OF CORNELL UNIV
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-05-15 至 2022-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10013829
关键词：
Address Age Aging Archives Bacterial Translocation Biological Markers Blood CD4 Lymphocyte Count CD4/CD8 ratio procedure Cardiovascular Diseases Chronic Clonal Expansion Cohort Studies Correlative Study Data Detection Development Endotoxins Epigenetic Process Epithelial Epithelium Ethnic Origin Exhibits Functional disorder Future Gastrointestinal tract structure General Population Goals Growth HIV HIV Infections HIV-1 HIV-2 Health Hematologic Neoplasms Hematopoiesis Hematopoietic System High Prevalence Human Human immunodeficiency virus test Impaired cognition Inflammaging Inflammation Inflammatory Interleukin-6 Intervention Studies Intestines Investigation Knowledge Lead Leaky Gut Malignant Neoplasms Measures Mutation Neurocognitive Participant Pathogenesis Pathway interactions Permeability Phenotype Physical Function Plasma Population Prevalence Preventive Intervention Process Race Recording of previous events Regulator Genes Research Personnel Role Somatic Mutation Specimen Testing The Multicenter AIDS Cohort Study Tight Junctions Toll-like receptors United States Viremia Woman Women’s Interagency HIV Study age related antiretroviral therapy circulating biomarkers cognitive function comorbidity data archive design frailty genetic variant immune activation interdisciplinary approach intestinal barrier men microbial mortality mouse model neurocognitive test next generation sequencing novel peripheral blood physically handicapped premalignant pressure sequencing platform sex stem cells targeted exome sequencing

项目摘要

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.

项目概要数据表明，患有此类疾病的人群中，合并症的患病率较高，并且衰老加剧或加速。艾滋病毒感染者 (PLWH)，包括虚弱和身体残疾的患病率较高。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，这些突变赋予竞争性生长优势——促进感染者炎症和衰老相关并发症未知。虽然一般人群中 CH 的患病率随着年龄的增长而增加，并且是潜在的预兆与心血管疾病和死亡率相关的恶性、促炎症状态，在与未感染 HIV 的对照组相比，我们对 PLWH 中 CH 的患病率和影响的了解。在小鼠中模型中，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 样受体依赖性引起 CH 克隆的内毒素反应性扩增途径。慢性艾滋病毒感染中肠道完整性受损的类似状态可能有利于 CH 克隆的扩展/持久性。我们的总体假设是 CH 在 PLWH 中更为普遍，并且导致老化加剧/加速。我们将采用多学科方法进行相关研究在人类中进行测试，以实现以下目标： 1) 测试 PLWH 中 CH 的患病率和数量是否升高与没有艾滋病毒的匹配对照相比； 2) 测试是否有认知障碍增加、虚弱、体力下降 CH 存在时的功能和炎症生物标志物。我们将使用来自以下机构的数据和存档样本多中心艾滋病项目的 500 名 55 岁及以上感染艾滋病毒的参与者和同等数量的未感染艾滋病毒的参与者队列研究-女性机构间艾滋病毒研究联合队列研究。没有 HIV 的对照将被匹配关于年龄、种族和民族。我们将使用靶向外显子组测序来检测血液中的 CH 突变正如我们之前在普通人群中进行的研究一样，>2% 的变异等位基因分数作为 CH 检测的阈值。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志物从存档的血浆样本中易位。我们新颖的探索性调查将产生重要数据为旨在了解衰老发病机制的更明确的人类研究的设计提供信息 PLWH 的相关并发症，将使未来的介入研究成为可能。