Aberrant DNA methylation of genes regulating CD4+ T cell HIV‐1 reservoir in women with HIV

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Background: The HIV‐1 reservoir in CD4+ T cells (HRCD4) pose a major challenge to curing HIV, with many of its mechanisms still unclear. HIV‐1 DNA integration and immune responses may alter the host's epigenetic landscape, potentially silencing HIV‐1 replication. Methods: This study used bisulphite capture DNA methylation sequencing in CD4+ T cells from the blood of 427 virally suppressed women with HIV to identify differentially methylated sites and regions associated with HRCD4. Results: The average total HRCD4 size was 1409 copies per million cells, with most proviruses defective and only a small proportion intact. The study identified 245 differentially methylated CpG sites and 85 regions linked to HRCD4 size, with 52% of significant sites in intronic regions. Genes associated with HRCD4 were involved in viral replication, HIV‐1 latency and cell growth and apoptosis. HRCD4 size was inversely related to DNA methylation of interferon signalling genes and positively associated with methylation at known HIV‐1 integration sites. HRCD4‐associated genes were enriched on the pathways related to immune defence, transcription repression and host–virus interactions. Conclusions: These findings suggest that HIV‐1 reservoir is linked to aberrant DNA methylation in CD4+ T cells, offering new insights into epigenetic mechanisms of HIV‐1 latency and potential molecular targets for eradication strategies.

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