Infection with human immunodeficiency virus type 1 upregulates DNA methyltransferase, resulting in de novo methylation of the gamma interferon (IFN-γ) promoter and subsequent downregulation of IFN-γ production

Judy A. Mikovits, Howard A. Young, Paula Vertino, Jean Pierre J Issa, Paula M. Pitha, Susan Turcoski-Corrales, Dennis D. Taub, Cari L. Petrow, Stephen B Baylin, Francis W. Ruscetti

Research output: Contribution to journalArticle

Abstract

The immune response to pathogens is regulated by a delicate balance of cytokines. The dysregulation of cytokine gene expression, including interleukin-12, tumor necrosis factor alpha, and gamma interferon (IFN-γ), following human retrovirus infection is well documented. One process by which such gene expression may be modulated is altered DNA methylation. In subsets of T-helper cells, the expression of IFN-γ, a cytokine important to the immune response to viral infection, is regulated in part by DNA methylation such that mRNA expression inversely correlates with the methylation status of the promoter. Of the many possible genes whose methylation status could be affected by viral infection, we examined the IFN-γ gene as a candidate. We show here that acute infection of cells with human immunodeficiency virus type 1 (HIV-1) results in (i) increased DNA methyltransferase expression and activity, (ii) an overall increase in methylation of DNA in infected cells, and (iii) the de novo methylation of a CpG dinucleotide in the IFN-γ gene promoter, resulting in the subsequent downregulation of expression of this cytokine. The introduction of an antisense methyltransferase construct into lymphoid cells resulted in markedly decreased methyltransferase expression, hypomethylation throughout the IFN-γ gene, and increased IFN-γ production, demonstrating a direct link between methyltransferase and IFN-γ gene expression. The ability of increased DNA methyltransferase activity to downregulate the expression of genes like the IFN-γ gene may be one of the mechanisms for dysfunction of T cells in HIV-1-infected individuals.

Original languageEnglish (US)
Pages (from-to)5166-5177
Number of pages12
JournalMolecular and Cellular Biology
Volume18
Issue number9
StatePublished - 1998

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Methyltransferases
Interferons
Methylation
Interferon-gamma
HIV-1
Up-Regulation
Down-Regulation
DNA
Infection
DNA Methylation
Cytokines
Gene Expression
Genes
Virus Diseases
Retroviridae Infections
Interleukin-12
Helper-Inducer T-Lymphocytes
Interferon-alpha
Tumor Necrosis Factor-alpha
Lymphocytes

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cell Biology

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Infection with human immunodeficiency virus type 1 upregulates DNA methyltransferase, resulting in de novo methylation of the gamma interferon (IFN-γ) promoter and subsequent downregulation of IFN-γ production. / Mikovits, Judy A.; Young, Howard A.; Vertino, Paula; Issa, Jean Pierre J; Pitha, Paula M.; Turcoski-Corrales, Susan; Taub, Dennis D.; Petrow, Cari L.; Baylin, Stephen B; Ruscetti, Francis W.

In: Molecular and Cellular Biology, Vol. 18, No. 9, 1998, p. 5166-5177.

Research output: Contribution to journalArticle

Mikovits, Judy A. ; Young, Howard A. ; Vertino, Paula ; Issa, Jean Pierre J ; Pitha, Paula M. ; Turcoski-Corrales, Susan ; Taub, Dennis D. ; Petrow, Cari L. ; Baylin, Stephen B ; Ruscetti, Francis W. / Infection with human immunodeficiency virus type 1 upregulates DNA methyltransferase, resulting in de novo methylation of the gamma interferon (IFN-γ) promoter and subsequent downregulation of IFN-γ production. In: Molecular and Cellular Biology. 1998 ; Vol. 18, No. 9. pp. 5166-5177.
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