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)使艾滋病毒感染得到了更好的控制，因此 提高艾滋病毒携带者(PWH)的存活率。这种日益增长的寿命已经转化为一种日益增长的慢性病 疾病负担，导致癌症现在成为威尔斯亲王医院的主要死亡原因。识别的生物标志物 因此，癌症风险最高的PWH需要量身定做早期检测计划，以改善这种增长 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，表观遗传时钟创造了不同于时间年龄(即出生)的生物年龄指标 年)。以前在非癌症环境中的研究已经证明，PWH具有估计的生物学意义 比个人实际年龄平均加速5年的年龄。我们的初步数据 表明这种表观遗传衰老的生物标志物在PWH患者中也不同于HIV阴性患者。 癌症诊断的时间。目前尚不清楚的是(1)艾滋病毒控制的程度是否与 使用现代表观遗传时钟的全谱来评估加速老化以及(2)这种老化是否 生物标记物在诊断为NADC的PWH与无癌PWH之间是唯一存在的。我们 假设PWH经历加速老化，这与HIV控制水平有关，或许更多 重要的是，加速衰老与癌症风险有关。为了检验这一假设，我们将利用400 从NCI赞助的艾滋病癌症标本资源(ACSR)到威斯康星医院的存档标本 完成评估艾滋病毒控制水平与加速生物反应之间关系的研究目标 老龄化(目标1)，并评估PWH中加速的生物衰老与NADC风险之间的关联 (目标2)。DNA将从全血、棕黄色大衣或PBMC样本中提取，DNA甲基化将被 使用Illumina甲基EPIC珠芯片进行检测。甲基组数据将被转换为 使用六个表观遗传时钟的生物衰老(例如，表观C2，这在以前的研究中没有得到评估)。为 目的1，我们将横断面比较100例PWH与病毒控制差(HIV病毒载量)之间的生物学年龄 10,000或CD4计数200)和100 PWH控制感染(HIV病毒载量100或CD 4计数350)， 在年龄和生理性别上相匹配。对于目标2，我们将比较100个PWH之间的生物年龄 在没有癌症诊断的ART患者(对照组)和100例有NADC诊断的PWH患者(病例)上， 在年龄和生理性别上相匹配。以探索性的方式，我们将描述生物的特征 莫菲特癌症中心确诊为肛门高度鳞状上皮内病变的50岁女性 HSIL)是肛门癌的先兆，50例PWH被诊断为浸润性肛门癌。我们预计这将是 研究将阐明艾滋病毒控制在多大程度上影响威斯康星医院加速的生物衰老 R01水平的努力，使用表观遗传老化生物标记物来识别患有NADCs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.