Abstract
BACKGROUND: Spontaneous control of HIV infection without anti-retroviral therapy (ART) is a rare phenomenon observed in a small subset of people living with HIV (PWH), yet its underlying mechanisms remain poorly understood. Epigenetic modifications, particularly DNA methylation, may contribute to this unique phenotype. METHODS: Here, we present an epigenome-wide association study (EWAS) analysing whole-blood DNA methylation profiles from the 2000HIV study, which includes HIV controllers (n = 111)-comprising elite controllers (ECs), viraemic controllers (VCs), transient controllers (TCs), and persistent controllers (PCs)- and virally suppressed PWH using ART (NHCs, n = 1667), from diverse ethnic backgrounds. The majority of participants (n = 1345) were of Western European descent, with additional representation from African and Asian populations. FINDINGS: We identified and replicated three genome-wide significant CpG sites (cg04784635, cg13131185, and cg07189782) (FDR <0.05) with overlapping methylation patterns across various HIV controllers subtypes, including ECs. However, these methylation patterns exhibited population-specific differences, including African and Asian. Additionally, differential methylation region analysis revealed that cg17974398 in the major histocompatibility complex (MHC) region may mediate the effect of the genetic variant rs3131018, potentially contributing to HIV control. INTERPRETATION: Our findings suggest that methylation near the MHC region may play an important role in HIV control and underscore the need for further investigation into population-specific epigenetic mechanisms. FUNDING: The work was conducted within the 2000HIV study, supported by ViiV Healthcare.