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

加速生物衰老在艾滋病毒控制和非艾滋病定义癌症风险中的作用（生物样本/生物队列）

• 批准号: 10619892
• 负责人: John L. Cleveland
• 金额: $ 10.42万
• 依托单位: H. LEE MOFFITT CANCER CTR & RES INST
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-02-18 至 2027-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10619892
• 关键词: AIDS/HIV problem; Acquired Immunodeficiency Syndrome; Address; Advanced Malignant Neoplasm; Age; Aging; Anus; Area; Biological; Biological Aging; Biological Assay; Biological Markers; Birth; CD4 Lymphocyte Count; Cancer Burden; Cancer Center; Cancer Patient; Cause of Death; Cell division; Chronic Disease; Chronology; Complement; DNA; DNA Methylation; Data; Diagnosis; Early Diagnosis; Epigenetic Process; Evaluation; Funding; Goals; HIV; HIV Infections; HIV Seronegativity; HIV diagnosis; High-Risk Cancer; Incidence; Individual; Infection; Knowledge; Light; Longevity; Malignant Neoplasms; Malignant neoplasm of anus; Methylation; Modernization; Outcome; Patients; Peripheral Blood Mononuclear Cell; Persons; Population; Research Priority; Resources; Risk; Role; Specimen; Squamous intraepithelial lesion; Testing; Time; Translating; United States National Institutes of Health; Viral; Viral Load result; Whole Blood; Work; age difference; aging population; antiretroviral therapy; bead chip; biological sex; biological specimen archives; burden of illness; cancer diagnosis; cancer risk; cancer specimen resource; co-infection; cohort; comorbidity; early screening; experience; human DNA; human old age (65+); improved; methylome; person centered; programs; screening program

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.

项目摘要。抗逆转录病毒疗法 (ART) 可以更好地控制 HIV 感染，因此 提高艾滋病毒感染者 (PWH) 的生存率。寿命的延长已转化为慢性病的增长 疾病负担，导致癌症现在成为感染者死亡的主要原因。识别的生物标志物 因此，患有癌症风险最高的感染者需要制定早期检测计划，以改善这种日益增长的癌症风险。 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，表观遗传时钟创建了与实际年龄不同的生物年龄指标（即出生 年）。先前在非癌症环境中的研究表明，PWH 具有估计的生物学效应。 年龄比个人的实际年龄平均提前 5 岁。我们的初步数据 表明，与艾滋病毒阴性患者相比，这种表观遗传衰老生物标志物在感染者中也存在差异。 癌症诊断的时间。目前尚不清楚的是（1）HIV 控制程度是否与 使用现代表观遗传时钟的全谱评估加速衰老，以及（2）这种衰老是否 与无癌症的 PWH 相比，生物标志物在 NADC 诊断的 PWH 中是独特存在的。我们 假设感染者经历了加速衰老，这与艾滋病毒控制水平有关，也许更多 重要的是，加速衰老与癌症风险相关。为了检验这个假设，我们将利用 400 从 NCI 赞助的艾滋病癌症样本资源 (ACSR) 中收集的 PWH 存档样本 完成研究目标，评估艾滋病毒控制水平与加速生物治疗之间的关系 衰老（目标 1）并评估 PWH 中加速生物衰老与 NADC 风险之间的关联 （目标 2）。从全血、血沉棕黄层或 PBMC 标本中提取 DNA，并进行 DNA 甲基化 使用 Illumina MmethylationEPIC BeadChip 进行测定。甲基组数据将被转换为以下指标： 使用六个表观遗传时钟（例如，epiTOC2，在之前的研究中尚未对其进行评估）进行生物衰老。为了 目标 1，我们将横断面比较病毒控制不佳（HIV 病毒载量）的 100 名感染者的生物学年龄 >10,000 或 CD4 计数 <200）和 100 PWH 感染受控（HIV 病毒载量 <100 或 CD4 计数 >350）， 实际年龄和生物性别相匹配。对于目标 2，我们将比较 100 名 PWH 之间的生物年龄 接受 ART 治疗但未诊断出癌症的患者（对照）和 100 名患有 NADC 诊断的 PWH（病例）， 实际年龄和生物性别相匹配。我们将以探索性的方式描述生物 50 岁的 PWH 在莫菲特癌症中心被诊断患有肛门高级鳞状上皮内病变（肛门 HSIL），肛门癌的前兆，50 名感染者被诊断患有侵袭性肛门癌。我们预计这 研究将揭示艾滋病毒控制对加速感染者生物衰老的影响程度，以激励 R01 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。