Infection of lymphoid cells by integration-defective human immunodeficiency virus type 1 increases de novo methylation.
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 p16(INK4A) 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 p16(INK4A) gene, silencing their expression.
Fang
J Y
JY
Basic Research Laboratory, CCR, National Cancer Institute at Frederick, Frederick, Maryland 21702, USA.
Mikovits
J A
JA
Bagni
R
R
Petrow-Sadowski
C L
CL
Ruscetti
F W
FW
D002460:Cell Line; D019175:DNA Methylation; D015254:DNA Modification Methylases / Q000235:genetics / Q000378:metabolism*; D015971:Gene Expression Regulation, Enzymologic; D019942:Genes, p16; D015497:HIV-1 / Q000201:enzymology / Q000235:genetics / Q000502:physiology*; D006801:Humans; D019426:Integrases / Q000172:deficiency / Q000235:genetics; D008214:Lymphocytes / Q000378:metabolism / Q000821:virology*; D009154:Mutation; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000032:analysis; D013997:Time Factors
D012333:RNA, Messenger; D015254:DNA Modification Methylases; D019426:Integrases