Objectives: HIV-1 modulates host cell epigenetic machinery to control its own replication and induce immune suppression. HIV-1 infection leads to activation of T regulatory cell (Treg), but the mechanism underlying this immune modulation is unclear. Treg plays a prominent role in gut-mucosal immune tolerance by restraining excessive effector T-cell responses, a mechanism that is known to be disturbed in chronic HIV-1 infection. DNA methylation plays a major role in Treg lineage commitment and immune homeostasis, which may be regulated by HIV. To investigate the mechanisms of aberrant methylation of the Treg marker FOXP3 in HIV-1 infection, we evaluated the expression pattern of methylation-related enzymes and its correlation to FOXP3 methylation.
Methods: FOXP3 promoter methylation in the colon mucosa and peripheral blood from HIV-infected patients and control subjects was measured using Pyrosequencing. Gene expression pattern of DNA methylation enzymes in the colon mucosa was investigated by Microarray and quantitative reverse transcriptase-polymerase chain reaction analysis in the same subjects.
Results: FOXP3 promoter was significantly (P ≤ 0.0001) demethylated in HIV-infected patients compared with control subjects in both tissues. Expression of DNA methyltransferase 1 (DNAMT1), DNA methyltransferase 1–associated protein 1(DMAP1), methyltransferase-like 7B (METTL7B), and methyltransferase-like 10 (METTL10) were significantly down regulated in HIV-infected patients compared with controls and had a significant positive correlation to FOXP3 promoter methylation.
Conclusions: We present evidence suggesting that altered methylation pattern of FOXP3 and accordingly higher Treg frequency in gut mucosa of HIV-infected patients may be because of aberrant methylation processing in HIV.
*Department of Internal Medicine, Division of Digestive Diseases, University of Cincinnati Medical Center, Cincinnati, OH; and
†Division of Asthma Research, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH.
Correspondence to: Enass A. Abdel-Hameed, MD, PhD, Viral Immunology Laboratory, MSB 6360, Department of Internal Medicine, Division of Digestive diseases, University of Cincinnati, College of Medicine, 231 Albert B. Sabin Way, Cincinnati, OH 45267 (e-mail: email@example.com).
Presented at HIV and Liver Diseases meeting, September 6–8, 2012, Jackson, WY and at 14th International meeting of Institution of Human Virology, October 14–17, 2012, Baltimore, MD.
Supported by Merck Investigator Initiated Studies Grant IISP 38879 (M.T.M.S.); National Institutes of Health Grant K24DK070528 (K.E.S.); and in part by Public Health Service Grant P30 DK078392 (The Gene Expression Microarray Core Cincinnati Children's Hospital Medical Center); National Institute of Health Grant NIH P30 DK078392 (Bioinformatics Core of the Digestive Disease Research Core Center in Cincinnati).
The authors have no conflicts of interest to disclose.
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Received April 04, 2013
Accepted June 21, 2013