Characterizing the Epigenetic relationship between aging, HIV-infection, ART and biological outcomes

表征衰老、HIV 感染、ART 和生物学结果之间的表观遗传关系

• 批准号: 9753079
• 负责人: Beth Deirdre Jamieson-Karavodin
• 金额: $ 69.63万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-01 至 2021-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9753079
• 关键词: Address; Adult; Age; Aging; Anal carcinoma; Biological; Biological Aging; Biological Markers; Biological Process; CD8-Positive T-Lymphocytes; Carcinoma; Cardiovascular Diseases; Caregivers; Cells; Cervix carcinoma; Chronic; Chronology; Clinical; Collection; Comorbidity; Complex; Control Groups; DNA Methylation; Data; Dependence; Development; Diabetes Mellitus; Disease; Enrollment; Environmental Risk Factor; Epigenetic Process; Ethnic Origin; Family; Future; Gait speed; Genes; Genetic; Goals; HIV; HIV Infections; HIV-1; Hand Strength; Health; Healthcare; Hepatitis C virus; Hypertension; Immune system; Impairment; Individual; Infection; Inflammaging; Inflammation; Inflammatory; Kidney; Kidney Diseases; Lead; Light; Link; Liver; Longevity; Mental Depression; Methylation; Molecular; Morbidity - disease rate; Natural History; Non-Hodgkin' s Lymphoma; Osteoporosis; Outcome; Pathogenesis; Pathway interactions; Pattern; Peripheral Blood Mononuclear Cell; Phenotype; Predisposition; Process; Race; Renal function; Reporting; Resources; Risk; Risk Factors; Role; Sampling; Smoking; Societies; Socioeconomic Status; T-Lymphocyte; Testing; The Multicenter AIDS Cohort Study; Therapeutic; Viral Load result; Work; age related; antiretroviral therapy; co-infection; cost; design; epigenetic therapy; epigenome; experimental study; frailty; functional decline; immune activation; infection risk; inflammatory marker; insight; liver function; longitudinal analysis; men; methylation pattern; mortality; new therapeutic target; novel; prognostic; prospective; public health relevance; senescence; theories

 DESCRIPTION (provided by applicant): While antiretroviral therapy (ART) has lengthened the life-span of HIV-1-infected individuals, even young treated adults are at increased risk of morbidity and mortality from health outcomes such as frailty, osteoporosis, cardiovascular disease, diabetes, various carcinomas and reduced renal and liver function, all of which are more common in older uninfected adults. These observations have led to speculation that HIV-1- infection, and perhaps even ART, accelerate aging. Despite the fact that aging is a complex, multisystem, biological process fraught with genetic variability and environmental factors, we successfully identified a pattern of DNA methylation that is strongly associated with aging, and is accelerated during HIV-1 infection by ~14 years. Our findings demonstrate that HIV-infection and aging have additive influence on overlapping epigenetic pathways, but the mechanisms by which these changes are triggered remain unclear. The accumulation of senescent and activated CD8+ T-cells, and increasing levels of inflammatory markers, are associated with increased risk of morbidity and mortality, suggesting that inflammatory processes may lie behind aging and HIV-associated epigenetic changes. The experiments we propose will investigate the relationship between ART, HIV-1-infection, aging, inflammation, and biological outcomes. The overall goal is to better define the mechanisms behind the increased risk for aging-related diseases in treated, HIV-infected adults. Specific Aim 1 will explore the ability of ART to restore epigenetic patterns to age-appropriate status, shedding light on the possible role of methylation as a pathway involved in aging and HIV-1-associated comorbidities, and providing novel insight into genes involved in aging and in HIV-1 and ART pathogenesis. Specific Aim 2 will explore the relationship between epigenetics, ART and biological outcomes such as grip strength and gait speed, two markers of biological aging known to be associated with functional decline, morbidity and mortality. Specific Aim 3 will further characterize the development of the aging-related methylation phenotype (ARMP) and explore the relationship between viral load and duration of infection on the ARMP. All three aims will explore associations between methylation status and levels of immune activation and inflammation. Genes implicated in poor biological outcomes can be explored later for associations with various comorbidities, and may provide new targets for novel therapeutic strategies to delay or mitigate the development of those health outcomes during aging with, and without, HIV-1-infection. As many of the comorbidities of aging and of HIV-1-infection result in significant costs to families and society, these experiments have strong

 描述(申请人提供)：虽然抗逆转录病毒疗法(ART)延长了HIV-1感染者的生命，但即使接受治疗的年轻成年人也面临更高的因健康后果而导致的发病率和死亡率的风险，如虚弱、骨质疏松症、心血管疾病、糖尿病、各种癌症以及肾和肝脏功能下降，所有这些都在未感染艾滋病毒的老年成年人中更为常见。这些观察结果引发了人们的猜测，即HIV-1感染，甚至ART，都会加速衰老。尽管衰老是一个复杂的、多系统的生物学过程，充满了遗传变异和环境因素，但我们成功地发现了一种与衰老密切相关的DNA甲基化模式，并在HIV-1感染期间加速了约14年。我们的发现表明，艾滋病毒感染和衰老对重叠的表观遗传途径具有相加的影响，但触发这些变化的机制尚不清楚。衰老和活化的CD8+T细胞的积累以及炎症标志物水平的增加与发病率和死亡率的增加相关，这表明炎症过程可能是衰老和HIV相关表观遗传学变化的原因。我们提出的实验将调查ART、HIV-1感染、衰老、炎症和生物学结果之间的关系。总体目标是更好地确定在接受治疗的艾滋病毒感染成年人中老年相关疾病风险增加背后的机制。具体目标1将探索ART修复的能力 表观遗传模式到适合年龄的状态，揭示甲基化作为参与衰老和HIV-1相关共病的途径的可能作用，并为涉及衰老和HIV-1和ART发病机制的基因提供新的见解。具体目标2将探索表观遗传学、ART和生物结果之间的关系，如握力和步速，这两个生物衰老的已知标记与功能衰退、发病率和死亡率有关。具体目标3将进一步表征衰老相关甲基化表型(ARMP)的发展，并探索ARMP上病毒载量和感染持续时间之间的关系。这三个目标都将探索甲基化状态与免疫激活和炎症水平之间的关系。与不良生物学结果有关的基因可以在以后探索与各种共病相关的基因，并可能为新的治疗策略提供新的靶点，以延缓或减轻在有或没有HIV-1感染的衰老过程中这些健康结果的发展。由于老龄化和HIV-1感染的许多并存会给家庭和社会带来巨大的成本，这些实验具有很强的