Cross-tissue study of an accelerated epigenetic aging mechanism caused by HIV

HIV引起的加速表观遗传衰老机制的跨组织研究

• 批准号: 8836838
• 负责人: Steve Horvath
• 金额: $ 23.1万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-15 至 2017-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8836838
• 关键词: Acceleration; Acquired Immunodeficiency Syndrome; Adult; Affect; Age; Aging; Anti-Retroviral Agents; Area; Atrophic; Biological Markers; Brain; California; Cell Aging; Cessation of life; Clinical; Cohort Studies; DNA Methylation; Data; Data Set; Development; Disease; Effectiveness; Enrollment; Epigenetic Process; Fibrosis; Foundations; Goals; HIV; HIV Infections; HIV diagnosis; Heart; Highly Active Antiretroviral Therapy; Human; Human body; Immune System Diseases; In Vitro; Incidence; Individual; Kidney; Lead; Leukocytes; Life Expectancy; Link; Liquid substance; Literature; Liver; Lung; Measures; Methods; Methylation; Molecular; Organ; Outcome; Participant; Pathology; Penetration; Peripheral Blood Mononuclear Cell; Pharmaceutical Preparations; Plasma; Population; Prognostic Marker; Research; Resolution; Sclerosis; Severity of illness; Survivors; System; Temporal Lobe; Testing; Therapeutic; Tissue Sample; Tissues; Universities; Viral Load result; Virus; Work; age effect; age related; aging population; base; body system; cell type; clinical effect; clinically relevant; epigenetic marker; epigenome; frontal lobe; frontier; genome-wide; human DNA; human tissue; methylation biomarker; neuroAIDS; novel; peripheral blood; public health relevance; skills; tissue resource; viral RNA

 DESCRIPTION (provided by applicant): Highly Active Antiretroviral Therapy (HAART) greatly reduces quantity of active virus and has resulted in a marked increase in life expectancy of HIV-infected (HIV+) individuals. While HAART has also led to a reduction in the incidence of AIDS-defining illnesses, a variety of HIV-Associated Non-AIDS (HANA) conditions more commonly associated with older age are increasingly commonplace in HIV+ individuals. Aging and HIV appear to share common features of immune dysfunction, and the two may act synergistically in the aging population with long term HIV infection. A burgeoning literature suggests that HIV infection accelerates aging; however the underlying molecular mechanisms remain poorly understood. In particular, it not known how measures of disease severity, such as HIV viral load, affect dynamic epigenetic processes such as DNA methylation (DNAm). It is also not known how long term use of HAART impacts DNAm. The PI recently developed a novel biomarker of aging (referred to as epigenetic clock), which is the first age prediction method based on DNAm levels that accurately predicts age in more than one human tissue or fluid. As a matter of fact, it works in the vast majority of tissues/fluids/organs. It is arguably the first accurate measure of age that allows one to compare the ages of different parts of the human body. Using two DNAm data sets from the peripheral blood mononuclear cells of HIV+ individuals, we have demonstrated that even low levels of HIV replication significantly accelerates age according to the epigenetic clock. This R21 proposal will generate crucial data for testing the plausible hypothesis that HIV viral load also accelerates aging in a wide variety of affected human tissues, thus helping to explain the higher incidence of HANA conditions affecting a variety of organ systems. The genome wide DNAm profiles will not only allow us to test this hypothesis but more broadly allow us to identify additional DNAm markers that correlate with viral load in different tissues. To study the clinical ramifications, we will correlate the methylation data with various markers of tissue pathology typically associated with aging (e.g., fibrosis), and pre-mortem diagnoses of HANA conditions. To study the effect of antiretroviral medication (ARV), we will correlate the methylation data with ARV usage data tracked up to 15 years pre-mortem while participants were enrolled in a longitudinal cohort study. This proposal leverages the tissue samples from deceased HIV+ and HIV- subjects and the latest version of the well-validated Ilumina Infinium 450K array, allowing high-resolution genome wide DNAm profiles. Our overarching goal is to show that accelerated cellular aging, as measured by DNAm, has clinical relevance in the context of HIV/HANA. Working from that foundation, we will further investigate the molecular mechanisms in in vitro systems. This research will lead to development of epigenetic biomarkers of HANA conditions, produce useful surrogate measures of clinical outcomes, and open up a new area for therapeutics.

 描述（由适用提供）：高度活跃的抗逆转录病毒疗法（HAART）大大减少了活性病毒的数量，并导致HIV感染（HIV+）个体的预期寿命显着增加。尽管HAART还导致了定义艾滋病疾病的发生率的降低，但在HIV+个体中，与年龄更大的各种艾滋病毒相关的非AID（HANA）疾病越来越普遍。衰老和艾滋病毒似乎具有免疫功能障碍的共同特征，两者可能在长期HIV感染的衰老人群中协同作用。 Brgeoning文献表明，HIV感染加速了衰老。但是，基本的分子机制仍然很少了解。特别是，尚不清楚疾病严重程度的测量（例如HIV病毒负荷）如何影响动态表观遗传过程，例如DNA甲基化（DNAM）。还不知道HAART会影响DNAM多长期使用。 PI最近开发了一种新型的衰老生物标志物（称为表观遗传时钟），这是基于DNAM水平的第一年龄预测方法，可以准确预测多种人体组织或液体中的年龄。事实上，它 在绝大多数组织/流体/器官中工作。可以说，这是对年龄的第一个准确测量，它可以比较人体不同部位的年龄。使用来自HIV+个体的外周血单核细胞中的两个DNAM数据集，我们证明，即使是较低的HIV复制，也可以根据表观遗传时钟显着加速年龄。该R21提案将产生至关重要的数据，以测试可见的假设，即HIV病毒负荷也加速了各种受影响的人体组织中的衰老，从而有助于解释影响各种器官系统的HANA条件的较高事件。基因组宽的DNAM轮廓不仅可以使我们能够检验这一假设，而且更广泛地使我们能够鉴定出与不同组织中病毒载荷相关的其他DNAM标记。为了研究临床分析，我们将将甲基化数据与 组织病理学的各种标记通常与衰老有关（例如纤维化）和HANA状况预诊断。为了研究抗逆转录病毒药物（ARV）的效果，我们将将甲基化数据与最多15年的ARV使用数据相关联，而参与者则参与了一项纵向队列研究。该建议利用已故的HIV+和HIV受试者的组织样本以及最新版本的已验证的Ilumina Infinium 450k阵列，从而允许高分辨率的基因组宽DNAM谱。我们的总体目标是证明DNAM测量的加速细胞衰老在HIV/HANA的背景下具有临床意义。我们将从该基金会工作，进一步研究体外系统中的分子机制。这项研究将导致HANA疾病的表观遗传生物标志物的发展，对临床结果进行有用的替代测量，并为新的治疗领域开放。