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

 描述(由申请人提供)：高效抗逆转录病毒疗法(HAART)大大减少了活跃病毒的数量，并显著延长了艾滋病毒感染者(HIV+)的预期寿命。虽然HAART也降低了艾滋病定义疾病的发病率，但在HIV+患者中，各种与艾滋病毒相关的非艾滋病(HANA)情况在艾滋病毒+患者中越来越常见，这种情况更常见于老年人。老龄化和艾滋病毒似乎具有免疫功能障碍的共同特征，在长期感染艾滋病毒的老龄化人口中，两者可能起协同作用。一篇新兴的文献表明，艾滋病毒感染会加速衰老；然而，其潜在的分子机制仍然知之甚少。特别是，它不知道衡量疾病严重程度的指标，如艾滋病毒病毒载量，如何影响动态表观遗传过程，如DNA甲基化(DNaM)。也不知道长期使用HAART会对dNaM产生多大影响。PI最近开发了一种新的衰老生物标志物(称为表观遗传学时钟)，这是第一种基于dNaM水平的年龄预测方法，可以准确预测不止一个人体组织或体液的年龄。事实上，它 在绝大多数组织/体液/器官中起作用。它可以说是第一个准确的年龄测量方法，可以让人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的两个dNaM数据集，我们已经证明，根据表观遗传学时钟，即使是低水平的HIV复制也会显著加速年龄。这项R21提案将产生关键数据，用于检验艾滋病毒病毒载量也会加速受影响的人体组织中的衰老这一合理假设，从而有助于解释影响各种器官系统的HANA疾病的较高发生率。全基因组dNaM图谱不仅允许我们检验这一假说，而且更广泛地允许我们识别与不同组织中的病毒载量相关的其他dNaM标记。为了研究临床结果，我们将甲基化数据与 组织病理学的各种标记物，通常与衰老(例如，纤维化)和HANA条件的尸前诊断有关。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参与者参加纵向队列研究时死亡前15年的ARV使用数据联系起来。这项建议利用了已故HIV+和HIV受试者的组织样本以及经过充分验证的ILumina Infinium450K阵列的最新版本，从而实现了高分辨率全基因组dNaM图谱。我们的首要目标是表明，由dNaM测量的细胞加速衰老在HIV/HANA的背景下具有临床相关性。在此基础上，我们将进一步研究体外系统中的分子机制。这项研究将导致开发HANA条件的表观遗传生物标记物，产生有用的临床结果替代措施，并为治疗学开辟一个新的领域。

 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.