Human immunodeficiency virus type 1 (HIV-1) modulates host cell epigenetic machinery to control its own replication cycle and induce immune suppression. The immunosuppression is reflected by the activation of the regulatory T-cell subset (Treg). DNA methylation of FOXP3 plays a major role in Treg lineage commitment and immune homeostasis. The aim of the current study is to investigate the mechanisms of aberrant methylation of FOXP3 by HIV-1 infection. Gene expression pattern of DNA methylation enzymes in the colon mucosa from HIV-infected patients and control subjects was investigated by Microarray analysis. FOXP3 promoter methylation in the same subjects was measured using Pyrosequencing. Our data indicated that FOXP3 promoter was significantly (p=< 0.0001) demethylated in HIV-infected patients compared to control subjects (% methylation 1.2 +/- 0.4 and 36.7 +/-1.6, respectively). Expression of DNA methyltransferase 1-associated protein 1(DMAP1), methyltransferase like 7B (METTL7B), and methyltransferase like 10 (METTL10), were significantly (p=0.028, 0.002, and 0.016 respectively) down regulated in HIV-infected patients compared to controls and had a significant positive correlation to FOXP3 promoter methylation (r= 0.89, p=0.001; r= 0.75, p= 0.017; r= 0.87, p=0.002 respectively). DMAP1is known to be a co-repressor that stimulates DNA methylation globally and locally, while the function of METTL7B and METTL10 is not yet well characterized. This study suggests possible mechanisms by which HIV may alter methylation pattern of FOXP3 in T reg and immune homeostasis.
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