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

Background: The HIV-1 reservoir in CD4+ T cells (HR) 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 HR.

Results: The average total HR 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 HR size, with 52% of significant sites in intronic regions. Genes associated with HR were involved in viral replication, HIV-1 latency and cell growth and apoptosis. HR size was inversely related to DNA methylation of interferon signalling genes and positively associated with methylation at known HIV-1 integration sites. HR-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.

Key Points: Study involved 427 women with HIV. Identified 245 aberrant DNA methylation sites and 85 methylation regions in CD4+ T cells linked to the HIV-1 reservoir. Highlighted genes are involved in viral replication, immune defence, and host genome integration. Findings suggest potential molecular targets for eradication strategies.