This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrowReprints and Permissions
Right arrow Copyright Information
Right arrow Books from ASM Press
Right arrow MicrobeWorld
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Mikovits, J. A.
Right arrow Articles by Ruscetti, F. W.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Mikovits, J. A.
Right arrow Articles by Ruscetti, F. W.

 Previous Article  |  Next Article 

Molecular and Cellular Biology, September 1998, p. 5166-5177, Vol. 18, No. 9
0270-7306/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.

Infection with Human Immunodeficiency Virus Type 1 Upregulates DNA Methyltransferase, Resulting in De Novo Methylation of the Gamma Interferon (IFN-gamma ) Promoter and Subsequent Downregulation of IFN-gamma Production

Judy A. Mikovits,1,* Howard A. Young,2 Paula Vertino,3 Jean-Pierre J. Issa,3 Paula M. Pitha,3 Susan Turcoski-Corrales,4 Dennis D. Taub,5 Cari L. Petrow,1 Stephen B. Baylin,3 and Francis W. Ruscetti6

Intramural Research Support Program, SAIC Frederick,1 and Laboratory of Experimental Immunology2 and Laboratory of Leukocyte Biology,6 Division of Basic Sciences, National Cancer Institute-Frederick Cancer Research and Development Center, Frederick Maryland 21702-1201; Oncology Center, The Johns Hopkins Medical Institutions, Baltimore, Maryland 212313; CBER, Rockville, Maryland 208924; and Laboratory of Immunology, National Institute of Aging, Baltimore, Maryland 212245

Received 3 March 1998/Returned for modification 28 April 1998/Accepted 23 June 1998

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-gamma ), 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-gamma , 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-gamma 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-gamma 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-gamma gene, and increased IFN-gamma production, demonstrating a direct link between methyltransferase and IFN-gamma gene expression. The ability of increased DNA methyltransferase activity to downregulate the expression of genes like the IFN-gamma gene may be one of the mechanisms for dysfunction of T cells in HIV-1-infected individuals.

* Corresponding author. Mailing address: P.O. Box B, Bldg. 567, Rm. 253, National Cancer Institute-Frederick Cancer Research and Development Center, Frederick, MD 21702-1201. Phone: (301) 846-5610. Fax: (301) 846-7034. E-mail: Mikovits{at}fcrfv1.ncifcrf.gov.

Molecular and Cellular Biology, September 1998, p. 5166-5177, Vol. 18, No. 9
0270-7306/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.


This article has been cited by other articles:

  • Humeniuk, R., Mishra, P. J., Bertino, J. R., Banerjee, D. (2009). Epigenetic reversal of acquired resistance to 5-fluorouracil treatment. Molecular Cancer Therapeutics 8: 1045-1054 [Abstract] [Full Text]  
  • Duverger, A., Jones, J., May, J., Bibollet-Ruche, F., Wagner, F. A., Cron, R. Q., Kutsch, O. (2009). Determinants of the Establishment of Human Immunodeficiency Virus Type 1 Latency. J. Virol. 83: 3078-3093 [Abstract] [Full Text]  
  • Liu, H., Li, H., Guo, L., Li, C., Li, M., Jiang, W., Liu, X., McNutt, M. A., Li, G. (2009). The mechanism involved in the repression of the {micro} opioid receptor gene expression in CEM x174 cells infected by simian immunodeficiency virus. J. Leukoc. Biol. 85: 684-691 [Abstract] [Full Text]  
  • Foley, D. L., Craig, J. M., Morley, R., Olsson, C. J., Dwyer, T., Smith, K., Saffery, R. (2009). Prospects for Epigenetic Epidemiology. Am J Epidemiol 169: 389-400 [Abstract] [Full Text]  
  • Li, F., Papworth, M., Minczuk, M., Rohde, C., Zhang, Y., Ragozin, S., Jeltsch, A. (2007). Chimeric DNA methyltransferases target DNA methylation to specific DNA sequences and repress expression of target genes. Nucleic Acids Res 35: 100-112 [Abstract] [Full Text]  
  • Shamay, M., Krithivas, A., Zhang, J., Hayward, S. D. (2006). Recruitment of the de novo DNA methyltransferase Dnmt3a by Kaposi's sarcoma-associated herpesvirus LANA. Proc. Natl. Acad. Sci. USA 103: 14554-14559 [Abstract] [Full Text]  
  • Chang, M.-S., Uozaki, H., Chong, J.-M., Ushiku, T., Sakuma, K., Ishikawa, S., Hino, R., Barua, R. R., Iwasaki, Y., Arai, K., Fujii, H., Nagai, H., Fukayama, M. (2006). CpG Island M;ethylation Status in Gastric Carcinoma with and without Infection of Epstein-Barr Virus.. Clin. Cancer Res. 12: 2995-3002 [Abstract] [Full Text]  
  • Bonilla-Henao, V., Martinez, R., Sobrino, F., Pintado, E. (2005). Different signaling pathways inhibit DNA methylation activity and up-regulate IFN-{gamma} in human lymphocytes. J. Leukoc. Biol. 78: 1339-1346 [Abstract] [Full Text]  
  • Shin, H.-J., Park, H.-Y., Jeong, S.-J., Park, H.-W., Kim, Y.-K., Cho, S.-H., Kim, Y.-Y., Cho, M.-L., Kim, H.-Y., Min, K.-U., Lee, C.-W. (2005). STAT4 Expression in Human T Cells Is Regulated by DNA Methylation but Not by Promoter Polymorphism. J. Immunol. 175: 7143-7150 [Abstract] [Full Text]  
  • Bream, J. H., Hodge, D. L., Gonsky, R., Spolski, R., Leonard, W. J., Krebs, S., Targan, S., Morinobu, A., O'Shea, J. J., Young, H. A. (2004). A Distal Region in the Interferon-{gamma} Gene Is a Site of Epigenetic Remodeling and Transcriptional Regulation by Interleukin-2. J. Biol. Chem. 279: 41249-41257 [Abstract] [Full Text]  
  • Mastronardi, F. G., Min, W., Wang, H., Winer, S., Dosch, M., Boggs, J. M., Moscarello, M. A. (2004). Attenuation of Experimental Autoimmune Encephalomyelitis and Nonimmune Demyelination by IFN-{beta} plus Vitamin B12: Treatment to Modify Notch-1/Sonic Hedgehog Balance. J. Immunol. 172: 6418-6426 [Abstract] [Full Text]  
  • Audige, A., Schlaepfer, E., Bonanomi, A., Joller, H., Knuchel, M. C., Weber, M., Nadal, D., Speck, R. F. (2004). HIV-1 Does Not Provoke Alteration of Cytokine Gene Expression in Lymphoid Tissue after Acute Infection Ex Vivo. J. Immunol. 172: 2687-2696 [Abstract] [Full Text]  
  • Yano, S., Ghosh, P., Kusaba, H., Buchholz, M., Longo, D. L. (2003). Effect of Promoter Methylation on the Regulation of IFN-{gamma} Gene During In Vitro Differentiation of Human Peripheral Blood T Cells into a Th2 Population. J. Immunol. 171: 2510-2516 [Abstract] [Full Text]  
  • McKay, P. F., Barouch, D. H., Schmitz, J. E., Veazey, R. S., Gorgone, D. A., Lifton, M. A., Williams, K. C., Letvin, N. L. (2003). Global Dysfunction of CD4 T-Lymphocyte Cytokine Expression in Simian-Human Immunodeficiency Virus/SIV-Infected Monkeys Is Prevented by Vaccination. J. Virol. 77: 4695-4702 [Abstract] [Full Text]  
  • Pion, M., Jordan, A., Biancotto, A., Dequiedt, F., Gondois-Rey, F., Rondeau, S., Vigne, R., Hejnar, J., Verdin, E., Hirsch, I. (2003). Transcriptional Suppression of In Vitro-Integrated Human Immunodeficiency Virus Type 1 Does Not Correlate with Proviral DNA Methylation. J. Virol. 77: 4025-4032 [Abstract] [Full Text]  
  • Issa, J.-P. (2002). Epigenetic Variation and Human Disease. J. Nutr. 132: 2388S-2392 [Abstract] [Full Text]  
  • Azzoni, L., Papasavvas, E., Chehimi, J., Kostman, J. R., Mounzer, K., Ondercin, J., Perussia, B., Montaner, L. J. (2002). Sustained Impairment of IFN-{gamma} Secretion in Suppressed HIV-Infected Patients Despite Mature NK Cell Recovery: Evidence for a Defective Reconstitution of Innate Immunity. J. Immunol. 168: 5764-5770 [Abstract] [Full Text]  
  • White, G. P., Watt, P. M., Holt, B. J., Holt, P. G. (2002). Differential Patterns of Methylation of the IFN-{gamma} Promoter at CpG and Non-CpG Sites Underlie Differences in IFN-{gamma} Gene Expression Between Human Neonatal and Adult CD45RO- T Cells. J. Immunol. 168: 2820-2827 [Abstract] [Full Text]  
  • Fang, J.-Y., Mikovits, J. A., Bagni, R., Petrow-Sadowski, C. L., Ruscetti, F. W. (2001). Infection of Lymphoid Cells by Integration-Defective Human Immunodeficiency Virus Type 1 Increases De Novo Methylation. J. Virol. 75: 9753-9761 [Abstract] [Full Text]  
  • Young, W.-B., Link, C. J. Jr. (2000). Chimeric Retroviral Helper Virus and Picornavirus IRES Sequence To Eliminate DNA Methylation for Improved Retroviral Packaging Cells. J. Virol. 74: 5242-5249 [Abstract] [Full Text]  
  • Grant, R. S., Naif, H., Thuruthyil, S. J., Nasr, N., Littlejohn, T., Takikawa, O., Kapoor, V. (2000). Induction of Indolamine 2,3-Dioxygenase in Primary Human Macrophages by Human Immunodeficiency Virus Type 1 Is Strain Dependent. J. Virol. 74: 4110-4115 [Abstract] [Full Text]  
  • Gollob, J. A., Mier, J. W., Veenstra, K., McDermott, D. F., Clancy, D., Clancy, M., Atkins, M. B. (2000). Phase I Trial of Twice-Weekly Intravenous Interleukin 12 in Patients with Metastatic Renal Cell Cancer or Malignant Melanoma: Ability to Maintain IFN-{{gamma}} Induction Is Associated with Clinical Response. Clin. Cancer Res. 6: 1678-1692 [Abstract] [Full Text]  
  • Young, W.-B., Lindberg, G. L., Link, C. J. Jr. (2000). DNA Methylation of Helper Virus Increases Genetic Instability of Retroviral Vector Producer Cells. J. Virol. 74: 3177-3187 [Abstract] [Full Text]  
  • Karpf, A. R., Peterson, P. W., Rawlins, J. T., Dalley, B. K., Yang, Q., Albertsen, H., Jones, D. A. (1999). Inhibition of DNA methyltransferase stimulates the expression of signal transducer and activator of transcription 1, 2, and 3 genes in colon tumor cells. Proc. Natl. Acad. Sci. USA 96: 14007-14012 [Abstract] [Full Text]  
  • Nuovo, G. J., Plaia, T. W., Belinsky, S. A., Baylin, S. B., Herman, J. G. (1999). In situ detection of the hypermethylation-induced inactivation of the p16 gene as an early event in oncogenesis. Proc. Natl. Acad. Sci. USA 96: 12754-12759 [Abstract] [Full Text]  
  • Fitzpatrick, D. R., Shirley, K. M., Kelso, A. (1999). Cutting Edge: Stable Epigenetic Inheritance of Regional IFN-{gamma} Promoter Demethylation in CD44highCD8+ T Lymphocytes. J. Immunol. 162: 5053-5057 [Abstract] [Full Text]  
  • Campanero, M. R., Armstrong, M. I., Flemington, E. K. (2000). CpG methylation as a mechanism for the regulation of E2F activity. Proc. Natl. Acad. Sci. USA 97: 6481-6486 [Abstract] [Full Text]  


Copyright © 2009 by the American Society for Microbiology.   For an alternate route to Journals.ASM.org, visit: http://intl-journals.asm.org | More Info»