The role of Accelerated Biological Aging in HIV control and Non-AIDS-defining Cancer Risk (Biospecimens/Biocohort)

项目摘要。抗逆转录病毒疗法（ART）已导致更好地控制艾滋病毒感染， 提高艾滋病毒感染者的生存率。这种寿命的增加已经转化为一种日益增长的慢性病， 癌症是威尔斯亲王医院的主要死因。生物标志物， 因此，癌症风险最高的PWH需要定制早期检测计划，以改善这种日益增长的 癌症负担随着年龄的增长，甲基化自然会在人类DNA上积累。使用甲基化 信息，表观遗传时钟创建与实足年龄不同的生物年龄的度量（即，出生 年）。先前在非癌症背景下的研究表明，PWH具有估计的生物学效应， 年龄比实际年龄平均快5岁。我们的初步数据 表明，这种表观遗传衰老生物标志物在PWH与HIV阴性患者之间也存在差异， 癌症诊断时间目前尚不清楚的是（1）艾滋病毒控制程度是否与 使用现代表观遗传时钟的全谱评估加速老化，以及（2）这种老化是否 与无癌PWH相比，生物标志物在呈现NADC诊断的PWH中唯一存在。我们 假设PWH经历加速老化，这与HIV控制水平有关，也许更多 重要的是，加速老化与癌症风险有关。为了验证这一假设，我们将利用400 PWH的存档标本来自NCI-sponsored AIDS Cancer Specimen Resource（ACSR）， 完成研究目的，评估艾滋病毒控制水平与加速生物学 老化（目标1），并评估PWH中加速生物老化与NADC风险之间的关联 (Aim 2）。将从全血、血沉棕黄层或PBMC标本中提取DNA，并将DNA甲基化进行分析。 使用Illumina MethylationEPIC BeadChip测定。甲基化组数据将被转化为 使用六个表观遗传时钟的生物老化（例如，epiTOC 2，其在先前的研究中未被评估）。为 目的1，我们将横断面比较生物年龄100 PWH与病毒控制不良（HIV病毒载量）之间的差异 &gt; 10，000或CD 4计数&lt;200）和100例感染得到控制的PWH（HIV病毒载量<100 or CD4 count >350）， 年龄和生理性别都匹配对于目标2，我们将比较100 PWH和100 PWH之间的生物年龄 接受ART的患者（对照组）和100例接受NADC诊断的PWH患者（例）， 年龄和生理性别都匹配在探索性的方式，我们将描述生物 一名50岁的PWH在莫菲特癌症中心被诊断为肛门高级鳞状上皮内病变（肛门 HSIL），肛门癌的前兆，和50名PWH诊断为浸润性肛门癌。我们预计， 这项研究将揭示艾滋病毒控制对威尔斯亲王医院加速生物衰老的影响程度， R 01级努力使用表观遗传衰老生物标志物来识别NADC风险增加的PWH。

PROJECT ABSTRACT. Antiretroviral therapy (ART) has led to better control of HIV infection and therefore improved survival for people with HIV (PWH). This increasing longevity has translated into a growing chronic disease burden, resulting in cancer now being a leading cause of death among PWH. Biomarkers that identify PWH at highest risk of cancer are therefore needed to tailor early detection programs to ameliorate this growing cancer burden. Methylation naturally accumulates on human DNA over time with aging. Using methylation information, epigenetic clocks create metrics of biological age that are distinct from chronological age (i.e., birth year). Previous studies in the non-cancer setting have demonstrated that PWH have an estimated biological age that is accelerated an average of 5 years beyond an individual’s chronological age. Our preliminary data indicate that this epigenetic aging biomarker also differs among PWH compared to HIV negative patients at the time of cancer diagnosis. What remains unknown is (1) whether the degree of HIV control is associated with accelerated aging as assessed using the full spectrum of modern epigenetic clocks and (2) whether this aging biomarker is uniquely present among PWH presenting with a NADC diagnosis vs cancer free PWH. We hypothesize that PWH experience accelerated aging that is related to the level of HIV control, and perhaps more importantly, that accelerated aging is associated with cancer risk. To test this hypothesis, we will leverage 400 archived specimens from PWH from the NCI-sponsored AIDS Cancer Specimen Resource (ACSR) to accomplish study aims that evaluate the association between level of HIV control and accelerated biological aging (Aim 1) and evaluate the association between accelerated biological aging and NADC risk among PWH (Aim 2). DNA will be extracted from whole blood, buffy coat, or PBMC specimens, and DNA methylation will be assayed using the Illumina MethylationEPIC BeadChip. Methylome data will be translated into a metric of biological aging using six epigenetic clocks (e.g., epiTOC2, which has not been evaluated in prior studies). For Aim 1, we will cross-sectionally compare biological age between 100 PWH with poor viral control (HIV viral load >10,000 or CD4 count <200) and 100 PWH with controlled infection (HIV viral load <100 or CD4 count >350), matched on chronological age and biological sex. For Aim 2, we will compare biological age between 100 PWH on ART who were followed without a cancer diagnosis (controls) and 100 PWH with a NADC diagnosis (cases), matched on chronological age and biological sex. In an exploratory manner, we will characterize the biological age of 50 PWH at Moffitt Cancer Center diagnosed with anal high-grade squamous intraepithelial lesions (anal HSIL), the precursor to anal cancer, and 50 PWH diagnosed with invasive anal cancer. We anticipate that this study will shed light on the degree to which HIV control impacts accelerated biological aging in PWH to motivate R01-level efforts to use epigenetic aging biomarkers to identify PWH at increased risk of NADCs.