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（由申请人提供）：高效抗逆转录病毒疗法（HAART）极大地减少了活性病毒的数量，并导致艾滋病毒感染者（HIV+）的预期寿命显着增加，同时HAART也导致了发病率的降低。在艾滋病定义的疾病中，各种与老年相关的非艾滋病 (HANA) 疾病在艾滋病病毒感染者中越来越常见，并且艾滋病毒似乎具有共同的特征。最新的文献表明，HIV 感染会加速衰老，但人们对这两种疾病的严重程度仍知之甚少。 HIV 病毒载量等会影响 DNA 甲基化 (DNAm) 等动态表观遗传过程。 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）。哪个是第一个基于 DNAm 水平的年龄预测方法，可以准确预测多个人体组织或体液的年龄。 它可以说是第一个准确的年龄测量方法，可以使用来自 HIV 阳性个体的外周血单核细胞的两个 DNAm 数据集来比较人体不同部位的年龄。 ，我们已经证明，根据表观遗传时钟，即使是低水平的 HIV 复制也会显着加速衰老，这一 R21 提案将为检验 HIV 病毒载量也会加速多种受影响的人体组织的衰老这一合理假设提供重要数据。来解释较高的发生率HANA 条件影响多种器官系统。全基因组 DNAm 谱不仅使我们能够检验这一假设，而且更广泛地使我们能够识别与不同组织中病毒载量相关的其他 DNAm 标记。将甲基化数据与 通常与衰老（例如纤维化）相关的各种组织病理学标志物以及 HANA 状况的死前诊断 为了研究抗逆转录病毒药物 (ARV) 的效果，我们将甲基化数据与长达 15 年的 ARV 使用数据进行关联。该提案利用了已故 HIV+ 和 HIV- 受试者的组织样本以及经过充分验证的 Ilumina Infinium 的最新版本。 450K 阵列，可实现高分辨率全基因组 DNAm 谱，我们的首要目标是证明通过 DNAm 测量的加速细胞衰老在 HIV/HANA 背景下具有临床意义，在此基础上，我们将进一步研究分子生物学。这项研究将促进 HANA 病症表观遗传生物标志物的开发，产生有用的临床结果替代指标，并开辟一个新的治疗领域。