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Epigenetic alterations are associated with monocyte immune dysfunctions in HIV-1 infection.

ABSTRACT: Monocytes are key cells in the immune dysregulation observed during human immunodeficiency virus (HIV) infection. The events that take place specifically in monocytes may contribute to the systemic immune dysfunction characterized by excessive immune activation in infected individuals, which directly correlates with pathogenesis and progression of the disease. Here, we investigated the immune dysfunction in monocytes from untreated and treated HIV + patients and associated these findings with epigenetic changes. Monocytes from HIV patients showed dysfunctional ability of phagocytosis and killing, and exhibited dysregulated cytokines and reactive oxygen species production after M. tuberculosis challenge in vitro. In addition, we showed that the expression of enzymes responsible for epigenetic changes was altered during HIV infection and was more prominent in patients that had high levels of soluble CD163 (sCD163), a newly identified plasmatic HIV progression biomarker. Among the enzymes, histone acetyltransferase 1 (HAT1) was the best epigenetic biomarker correlated with HIV - sCD163 high patients. In conclusion, we confirmed that HIV impairs effector functions of monocytes and these alterations are associated with epigenetic changes that once identified could be used as targets in therapies aiming the reduction of the systemic activation state found in HIV patients.

SUBMITTER: Espindola MS

PROVIDER: S-EPMC5882962 | biostudies-literature | 2018 Apr

REPOSITORIES: biostudies-literature

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Epigenetic alterations are associated with monocyte immune dysfunctions in HIV-1 infection.

Espíndola Milena S MS Soares Luana S LS Galvão-Lima Leonardo J LJ Zambuzi Fabiana A FA Cacemiro Maira C MC Brauer Verônica S VS Marzocchi-Machado Cleni M CM de Souza Gomes Matheus M Amaral Laurence R LR Martins-Filho Olindo A OA Bollela Valdes R VR Frantz Fabiani G FG

Scientific reports 20180403 1

Monocytes are key cells in the immune dysregulation observed during human immunodeficiency virus (HIV) infection. The events that take place specifically in monocytes may contribute to the systemic immune dysfunction characterized by excessive immune activation in infected individuals, which directly correlates with pathogenesis and progression of the disease. Here, we investigated the immune dysfunction in monocytes from untreated and treated HIV + patients and associated these findings with ep ...[more]

PMID: 29615725

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Project description:Background and methods: Host genomic alterations are closely related to dysfunction of CD4+ T lymphocytes in the HIV-host interplay. However, the roles of aberrant DNA methylation and gene expression in the response to HIV infection are not fully understood. We investigated the genome-wide DNA methylation and transcriptomic profiles in two HIV-infected T lymphocyte cell lines using high-throughput sequencing. Results: Based on DNA methylation data, we identified 3,060 hypomethylated differentially methylated regions (DMRs) and 2,659 hypermethylated DMRs in HIV-infected cells. Transcription-factor-binding motifs were significantly associated with methylation alterations, suggesting that DNA methylation modulates gene expression by affecting the binding to transcription factors during HIV infection. In support of this hypothesis, genes with promoters overlapping with DMRs were enriched in the biological function related to transcription factor activities. Furthermore, the analysis of gene expression data identified 1,633 upregulated genes and 2,142 downregulated genes on average in HIV-infected cells. These differentially expressed genes (DEGs) were significantly enriched in apoptosis-related pathways. Our results suggest alternative splicing as an additional mechanism that may contribute to T-cell apoptosis during HIV infection. We also demonstrated a genome-scale correlation between DNA methylation and gene expression in HIV-infected cells. We identified 831 genes with alterations in both DNA methylation and gene expression, which were enriched in apoptosis. Our results were validated using various experimental methods. In addition, consistent with our in silico results, a luciferase assay showed that the activity of the PDX1 and SMAD3 promoters was significantly decreased in the presence of HIV proteins, indicating the potential of these genes as genetic markers of HIV infection. Conclusions: Our results suggest important roles for DNA methylation and gene expression regulation in T-cell apoptosis during HIV infection. We propose a list of novel genes related to these processes for further investigation. This study also provides a comprehensive characterization of changes occurring at the transcriptional and epigenetic levels in T cells in response to HIV infection.

Dataset Information

Epigenetic alterations are associated with monocyte immune dysfunctions in HIV-1 infection.

Publications

Epigenetic alterations are associated with monocyte immune dysfunctions in HIV-1 infection.

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