INFECTION WITH HUMAN-IMMUNODEFICIENCY-VIRUS TYPE-1 UP-REGULATES DNA METHYLTRANSFERASE, RESULTING IN DE-NOVO METHYLATION OF THE GAMMA-INTERFERON (IFN-GAMMA) PROMOTER AND SUBSEQUENT DOWN-REGULATION OF IFN-GAMMA PRODUCTION

The immune response to pathogens is regulated by a delicate balance of cytokines. The dysregulation of cytokine gene expression, including i nterleukin-12 tumor necrosis factor alpha, and gamma interferon (IFN-g amma), following human retrovirus infection is well documented. One pr ocess by which such gene expression may be modulated is altered DNA me thylation. In subsets of T-helper cells, the expression of IFN-gamma, a cytokine important to the immune response to viral infection, is reg ulated in part by DNA methylation such that mRNA expression inversely correlates with the methylation status of the promoter. Of the many po ssible genes whose methylation status could be affected by viral infec tion, we examined the IFN-gamma gene as a candidate. We show here that acute infection of cells with human immunodeficiency virus type 1 (HI V 1) results in (i) increased DNA methyltransferase expression and act ivity, (ii) an overall increase in methylation of DNA in infected cell s, and (iii) the de novo methylation of a CpG dinucleotide in the IFN- gamma gene promoter, resulting in the subsequent downregulation of exp ression of this cytokine. The introduction of an antisense methyltrans ferase construct into lymphoid cells resulted in markedly decreased me thyltransferase expression, hypomethylation throughout the IFN-gamma g ene, and increased IFN-gamma production, demonstrating a direct link b etween methyltransferase and IFN-gamma gene expression. The ability of increased DNA methyltransferase activity to downregulate the expressi on of genes like the IFN-gamma gene may be one of the mechanisms for d ysfunction of T cells in HIV-1-infected individuals.