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Journal of Virology, October 2001, p. 9753-9761, Vol. 75, No. 20
0022-538X/01/$04.00+0   DOI: 10.1128/JVI.75.20.9753-9761.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

Infection of Lymphoid Cells by Integration-Defective Human Immunodeficiency Virus Type 1 Increases De Novo Methylation

Jing-Yuan Fang,1 Judy A. Mikovits,2,3,dagger Rachel Bagni,4 Cari L. Petrow-Sadowski,4 and Francis W. Ruscetti1,*

Basic Research Laboratory, CCR, National Cancer Institute at Frederick,1 Laboratory of Antiviral Drug Mechanisms2 and Intramural Research Support Program,4 SAIC Frederick, and Developmental Therapeutics Program, DCTP,3 Frederick, Maryland 21702

Received 21 November 2000/Accepted 13 July 2001

DNA methylation, by regulating the transcription of genes, is a major modifier of the eukaryotic genome. DNA methyltransferases (DNMTs) are responsible for both maintenance and de novo methylation. We have reported that human immunodeficiency virus type 1 (HIV-1) infection increases DNMT1 expression and de novo methylation of genes such as the gamma interferon gene in CD4+ cells. Here, we examined the mechanism(s) by which HIV-1 infection increases the cellular capacity to methylate genes. While the RNAs and proteins of all three DNMTs (1, 3a, and 3b) were detected in Hut 78 lymphoid cells, only the expression of DNMT1 was significantly increased 3 to 5 days postinfection. This increase was observed with either wild-type HIV-1 or an integrase (IN) mutant, which renders HIV replication defective, due to the inability of the provirus to integrate into the host genome. Unintegrated viral DNA is a common feature of many retroviral infections and is thought to play a role in pathogenesis. These results indicate another mechanism by which unintegrated viral DNA affects the host. In addition to the increase in overall genomic methylation, hypermethylation and reduced expression of the p16INK4A gene, one of the most commonly altered genes in human cancer, were seen in cells infected with both wild-type and IN-defective HIV-1. Thus, infection of lymphoid cells with integration-defective HIV-1 can increase the methylation of CpG islands in the promoters of genes such as the p16INK4A gene, silencing their expression.

* Corresponding author. Mailing address: Basic Research Laboratory, Bldg. 567, Rm. 253, National Cancer Institute at Frederick, Frederick, MD 21702-1201. Phone: (301) 846-5610. Fax: (301) 846-7034. E-mail: ruscettif{at}mail.ncifcrf.gov.

dagger Present address: EpiGenX Pharmaceuticals, Santa Barbara, Calif.

Journal of Virology, October 2001, p. 9753-9761, Vol. 75, No. 20
0022-538X/01/$04.00+0   DOI: 10.1128/JVI.75.20.9753-9761.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


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