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

Abstract

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

Prospects for Epigenetic Epidemiology

“…Insulin-like growth factor 2 methylation imprinting profile in the placenta is altered in mice infected with Campylobacter rectus during pregnancy (142). Similar alterations in DNA methylation have been reported in human cells and cell lines following viral or helminth infection (146)(147)(148)(149)(150)(151)(152). Methylation may be increased or decreased depending on the infectious agent (142,153).…”

Epigenetic changes in virus-associated human cancers

“…However, whether this methylation event has preference on certain genes remains unknown. In addition to SV40 and EBV, infection of HIV also causes upregulation of the DNMT1 protein expression [67,68]. This activation in turn elevated the global genomic methylation and on the other hand suppressed other genes expression such as interferon-γ (IFN-γ), a cytokine important for immune response during virus infection [67], and p16 INK4 , a common altered tumor suppressor gene found in cancers.…”

SIVMAC Vpx improves the transduction of dendritic cells with nonintegrative HIV-1-derived vectors

“…To circumvent this problem, several groups have evaluated the use of integration-incompetent LVs. [3][4][5][6][7][8] Gene expression from these vectors is driven from viral DNA molecules that remain in an episomal form after their entry into the nucleus as 1 or 2 long terminal repeat circles (1-or 2-LTRs, respectively). These episomes are considered as a deadend product in the normal retroviral infection process, but they are a functional substrate for the transcriptional machinery.…”