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

Abstract

Background

The HIV-1 reservoir in CD4+ T cells (HR_CD4) 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_CD4.

Results

The average total HR_CD4 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_CD4 size, with 52% of significant sites in intronic regions. Genes associated with HR_CD4 were involved in viral replication, HIV-1 latency and cell growth and apoptosis. HR_CD4 size was inversely related to DNA methylation of interferon signalling genes and positively associated with methylation at known HIV-1 integration sites. HR_CD4-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.