Epigenetic modification of FOXP3 in patients with chronic HIV infection

• Published in: Journal of acquired immune deficiency syndromes (1999) Vol. 65; no. 1; p. 19
• Main Authors: Abdel-Hameed, Enass A, Ji, Hong, Sherman, Kenneth E, Shata, Mohamed T M
• Format: Journal Article
• Language: English
• Published: United States 01.01.2014
• Subjects: Adult; Case-Control Studies; Colon - metabolism; DNA Methylation - physiology; Epigenesis, Genetic - physiology; Female; Forkhead Transcription Factors - metabolism; Forkhead Transcription Factors - physiology; HIV Infections - immunology; HIV Infections - physiopathology; HIV-1 - physiology; Humans; Intestinal Mucosa - metabolism; Male; Middle Aged; Oligonucleotide Array Sequence Analysis; Reverse Transcriptase Polymerase Chain Reaction; T-Lymphocytes, Regulatory - physiology; Transcriptome - physiology; Young Adult
• ISSN: 1944-7884
• DOI: 10.1097/QAI.0b013e3182a1bca4

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 (T(reg)), but the mechanism underlying this immune modulation is unclear. T(reg) 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 T(reg) lineage commitment and immune homeostasis, which may be regulated by HIV. To investigate the mechanisms of aberrant methylation of the T(reg) marker FOXP3 in HIV-1 infection, we evaluated the expression pattern of methylation-related enzymes and its correlation to FOXP3 methylation. 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. 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. We present evidence suggesting that altered methylation pattern of FOXP3 and accordingly higher T(reg) frequency in gut mucosa of HIV-infected patients may be because of aberrant methylation processing in HIV.