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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.
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BACKGROUND: This study aimed to explore the active ingredients and potential mechanism of our hospital's Guillain-Barré syndrome (GBS) experiential prescription in the treatment of GBS based on network pharmacology. METHODS: The traditional Chinese medicine system pharmacology (TCMSP) database was used to screen the active ingredients of the eight traditional Chinese medicines (TCMs) of the GBS-experiential prescription, and the Online Mendelian Inheritance in Man (OMIM), GeneCards, and MalaCards databases were used to obtain GBS-related gene targets. The common targets of the experiential prescriptions and GBS-related gene targets were acquired and imported into the STRING database to obtain the protein interaction relationship. Gene oncology (GO) function and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were performed to predict the major mechanism of this prescription. RESULTS: The formula contained at least 154 potential active ingredients and a total of 4,270 unique targets, among which a total of 158 GBS-related disease targets and 70 common targets were found. The key targets included EGFR (Epidermal Growth Factor Receptor), TNF (Tumor Necrosis Factor), ITGAL (Integrin Subunit Alpha L), and CEBPA (CCAAT/Enhancer-Binding Protein Alpha), CPT2 (Carnitine Palmitoyltransferase 2), CRP (C-reactive protein), ICAM1 (Intercellular Adhesion Molecule 1), IL6 (interleukin 6), and PECAM1 (Platelet and Endothelial Cell Adhesion Molecule 1), CREBBP (CREB Binding Protein), etc. The GO enrichment analysis results revealed 116 terms, and the KEGG signaling pathway enrichment analysis results yielded 61 pathways, including influenza A, hepatitis B, malaria, etc. CONCLUSIONS: The development of GBS and the mechanism underlying the effects of the GBS-experiential prescription have common and complex targets, which are worthy of in-depth exploration.