Abstract
BackgroundIntegration of human immunodeficiency virus type 1 (HIV-1) into the host genome causes global disruption of the chromatin environment. The abundance level of various chromatin-modifying enzymes produces these alterations and affects both the provirus and cellular gene expression. Here, we investigated potential changes in enzyme expression and global DNA methylation in chronically infected individuals with HIV-1 and compared these changes with non-HIV infected individuals. We also evaluated the effect of viral replication and degree of disease progression over these changes.ResultsIndividuals with HIV-1 had a significant surge in the expression of DNA and histone methyltransferases (DNMT3A and DNMT3B, SETDB1, SUV39H1) compared with non-infected individuals, with the exception of PRMT6, which was downregulated. Some histone deacetylases (HDAC2 and HDAC3) were also upregulated in patients with HIV. Among individuals with HIV-1 with various degrees of progression and HIV control, the group of treated patients with undetectable viremia showed greater differences with the other two groups (untreated HIV-1 controllers and non-controllers). These latter two groups exhibited a similar behavior between them. Of interest, the overexpression of genes that associate with viral protein Tat (such as SETDB1 along with DNMT3A and HDAC1, and SIRT-1) was more prevalent in treated patients. We also observed elevated levels of global DNA methylation in individuals with HIV-1 in an inverse correlation with the CD4/CD8 ratio.ConclusionsThe current study shows an increase in chromatin-modifying enzymes and remodelers and in global DNA methylation in patients with chronic HIV-1 infection, modulated by various levels of viral control and progression.
Highlights
Integration of human immunodeficiency virus type 1 (HIV-1) into the host genome causes global disruption of the chromatin environment
The proviral long terminal repeat (LTR) promoter is complexed with two nucleosomes that can modify their conformation through binding of multimolecular complexes of histone acetyltransferases (HATs), histone deacetyltransferases (HDACs), and other enzymes
The highest difference was observed for HDAC2, with over sixfold upregulation in patients with HIV-1
Summary
Integration of human immunodeficiency virus type 1 (HIV-1) into the host genome causes global disruption of the chromatin environment. Chromatin is a highly dynamic structure that, during human immunodeficiency virus (HIV) infection, is altered by the viral integration into the host genome and the host immune response that follows. This virus-host interaction creates an epigenetic environment with a two-way effect. T lymphocyte gene expression is modulated to create a cellular environment that favors the establishment of infection, promotes viral replication, and facilitates viral persistence. These chromatin changes are directed by a wide battery of chromatin-modifying enzymes and DNAassociated proteins. This process suggests a complex interaction of Tat with host epigenetic mechanisms, with various effects dependent on Tat concentration and possibly disease stage
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