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Abstract：
Introduction: Highly active antiretroviral therapy (HAART) helps improve some measures of accelerated epigenetic aging in persons living with HIV (PLWH), but its overall impact on the epigenome is not fully understood. Methods: In this study, we analyzed the DNA methylation profiles of PLWH (n = 187) shortly before and approximately 2-3 years after they started HAART, as well as matched seronegative (SN) controls (n = 187), taken at two time intervals. Our aim was to identify specific CpGs and biologic pathways associated with HIV infection and initiation of HAART. Additionally, we attempted to identify epigenetic changes associated with HAART initiation that were independent of HIV-associated changes, using matched HIV seronegative (SN) controls (matched on age, hepatitis C status, and interval between visits) to identify CpGs that did not differ between PLWH and SN pre-HAART but were significantly associated with HAART initiation while being unrelated to HIV viral load. Epigenome-wide association studies (EWAS) on >850,000 CpG sites were performed using pre- and post-HAART samples from PLWH. The results were then annotated using the Genomic Regions Enrichment of Annotations Tool (GREAT). Results: When only pre- and post-HAART visits in PLWH were compared, gene ontologies related to immune function and diseases related to immune function were significant, though with less significance for PLWH with detectable HIV viral loads (>50 copies/mL) at the post-HAART visit. To specifically elucidate the effects of HAART separately from HIV-induced methylation changes, we performed EWAS of HAART while also controlling for HIV viral load, and found gene ontologies associated with transplant rejection, transplant-related diseases, and other immunologic signatures. Additionally, we performed a more focused analysis that examined CpGs reaching genome-wide significance (p < 1 × 10-7) from the viral load-controlled EWAS that did not differ between all PLWH and matched SN controls pre-HAART. These CpGs were found to be near genes that play a role in retroviral drug metabolism, diffuse large B cell lymphoma proliferation, and gastric cancer metastasis. Discussion: Overall, this study provides insight into potential biological functions associated with DNA methylation changes induced by HAART initiation in persons living with HIV.
摘要：
简介：高效抗逆转录病毒疗法（HAART）有助于改善HIV感染者（PLWH）加速表观遗传衰老的一些措施，但其对表观基因组的总体影响尚未完全了解。方法:在本研究中,我们分析了PLWH（n=187）在开始HAART前不久和大约2-3年后的DNA甲基化谱，以及匹配的血清阴性（SN）对照（n=187），采取两个时间间隔。我们的目的是确定与HIV感染和HAART启动相关的特定CpG和生物学途径。此外,我们试图确定与HAART启动相关的表观遗传变化，这些变化独立于HIV相关变化，使用匹配的HIV血清阴性(SN)对照(年龄匹配，丙型肝炎状态，和访问之间的间隔），以确定CPG在PLWH和SN之间在HAART前没有差异，但与HAART启动显着相关，而与HIV病毒载量无关。使用来自PLWH的HAART前和后样品对>850,000个CpG位点进行全基因组关联研究(EWAS)。然后使用基因组区域富集注释工具(GREAT)对结果进行注释。结果：当仅比较PLWH的HAART前后访视时，与免疫功能相关的基因本体和与免疫功能相关的疾病显著,尽管在HAART访视后可检测到HIV病毒载量（>50拷贝/mL）的PLWH的意义较小。为了明确阐明HAART与HIV诱导的甲基化变化的作用，我们进行了HAART的EWAS，同时还控制了HIV病毒载量，发现了与移植排斥相关的基因本体论，移植相关疾病,和其他免疫特征。此外,我们进行了更集中的分析,检查了来自病毒载量控制的EWAS的达到全基因组显著性(p<1×10-7)的CpG,在HAART前,所有PLWH和匹配的SN对照之间没有差异.这些CpG被发现在逆转录病毒药物代谢中起作用的基因附近，弥漫性大B细胞淋巴瘤,和胃癌转移。讨论：总的来说，这项研究提供了与HIV感染者中HAART起始诱导的DNA甲基化变化相关的潜在生物学功能。
