Zhang Joshua, Sehl Mary E, Shih Roger, Breen Elizabeth Crabb, Li Fengxue, Lu Ake T, Bream Jay H, Duggal Priya, Martinson Jeremy, Wolinsky Steven M, Martinez-Maza Otoniel, Ramirez Christina M, Horvath Steve, Jamieson Beth D
Department of Human Genetics, David Geffen School of Medicine at UCLA, University of California Los Angeles, Los Angeles, CA, United States.
Division of Hematology-Oncology, Department of Medicine, David Geffen School of Medicine at UCLA, University of California Los Angeles, Los Angeles, CA, United States.
Front Bioinform. 2024 May 24;4:1357889. doi: 10.3389/fbinf.2024.1357889. eCollection 2024.
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. In this study, we analyzed the DNA methylation profiles of PLWH ( = 187) shortly before and approximately 2-3 years after they started HAART, as well as matched seronegative (SN) controls ( = 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). 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 ( < 1 × 10) 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. Overall, this study provides insight into potential biological functions associated with DNA methylation changes induced by HAART initiation in persons living with HIV.
高效抗逆转录病毒疗法（HAART）有助于改善部分HIV感染者（PLWH）加速表观遗传衰老的一些指标，但其对表观基因组的总体影响尚未完全明确。在本研究中，我们分析了187例PLWH在开始HAART之前不久以及开始HAART后约2 - 3年时的DNA甲基化谱，以及在两个时间间隔采集的187例配对血清阴性（SN）对照的DNA甲基化谱。我们的目的是确定与HIV感染及开始HAART相关的特定CpG位点和生物学途径。此外，我们试图通过使用配对的HIV血清阴性（SN）对照（在年龄、丙型肝炎状态和就诊间隔方面进行匹配）来识别与HAART开始相关的、独立于HIV相关变化的表观遗传变化，以确定在HAART前PLWH和SN之间无差异但与HAART开始显著相关且与HIV病毒载量无关的CpG位点。使用PLWH的HAART前和HAART后样本对超过85万个CpG位点进行了全表观基因组关联研究（EWAS）。然后使用基因组区域注释富集工具（GREAT）对结果进行注释。当仅比较PLWH的HAART前和HAART后就诊情况时，与免疫功能相关的基因本体以及与免疫功能相关的疾病是显著的，不过对于在HAART后就诊时可检测到HIV病毒载量（>50拷贝/mL）的PLWH，其显著性较低。为了具体阐明HAART的影响，将其与HIV诱导的甲基化变化分开，我们在控制HIV病毒载量的同时对HAART进行了EWAS，发现了与移植排斥、移植相关疾病和其他免疫特征相关的基因本体。此外，我们进行了更有针对性的分析，检查了在病毒载量控制的EWAS中达到全基因组显著性（<1×10）的CpG位点，这些位点在所有PLWH和配对的SN对照HAART前无差异。发现这些CpG位点靠近在逆转录病毒药物代谢、弥漫性大B细胞淋巴瘤增殖和胃癌转移中起作用的基因。总体而言，本研究深入了解了与HIV感染者开始HAART诱导的DNA甲基化变化相关的潜在生物学功能。
