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      Control of viral infections by epigenetic-targeted therapy

      review-article
      1 , 2 , 1 , 1 , 3 ,
      Clinical Epigenetics
      BioMed Central
      Virus, HIV, HCMV, Epigenetics, Treatment, Cancer

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          Abstract

          Epigenetics is defined as the science that studies the modifications of gene expression that are not owed to mutations or changes in the genetic sequence. Recently, strong evidences are pinpointing toward a solid interplay between such epigenetic alterations and the outcome of human cytomegalovirus (HCMV) infection. Guided by the previous possibly promising experimental trials of human immunodeficiency virus (HIV) epigenetic reprogramming, the latter is paving the road toward two major approaches to control viral gene expression or latency. Reactivating HCMV from the latent phase (“shock and kill” paradigm) or alternatively repressing the virus lytic and reactivation phases (“block and lock” paradigm) by epigenetic-targeted therapy represent encouraging options to overcome latency and viral shedding or otherwise replication and infectivity, which could lead eventually to control the infection and its complications. Not limited to HIV and HCMV, this concept is similarly studied in the context of hepatitis B and C virus, herpes simplex virus, and Epstein-Barr virus. Therefore, epigenetic manipulations stand as a pioneering research area in modern biology and could constitute a curative methodology by potentially consenting the development of broad-spectrum antivirals to control viral infections in vivo.

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          Most cited references156

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          HIV: Shock and kill.

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            Transcription factor YY1: structure, function, and therapeutic implications in cancer biology.

            The ubiquitous transcription factor Yin Yang 1 (YY1) is known to have a fundamental role in normal biologic processes such as embryogenesis, differentiation, replication, and cellular proliferation. YY1 exerts its effects on genes involved in these processes via its ability to initiate, activate, or repress transcription depending upon the context in which it binds. Mechanisms of action include direct activation or repression, indirect activation or repression via cofactor recruitment, or activation or repression by disruption of binding sites or conformational DNA changes. YY1 activity is regulated by transcription factors and cytoplasmic proteins that have been shown to abrogate or completely inhibit YY1-mediated activation or repression; however, these mechanisms have not yet been fully elucidated. Since expression and function of YY1 are known to be intimately associated with progression through phases of the cell cycle, the physiologic significance of YY1 activity has recently been applied to models of tumor biology. The majority of the data are consistent with the hypothesis that YY1 overexpression and/or activation is associated with unchecked cellular proliferation, resistance to apoptotic stimuli, tumorigenesis and metastatic potential. Studies involving hematopoetic tumors, epithelial-based tumors, endocrine organ malignancies, hepatocellular carcinoma, and retinoblastoma support this hypothesis. Molecular mechanisms that have been investigated include YY1-mediated downregulation of p53 activity, interference with poly-ADP-ribose polymerase, alteration in c-myc and nuclear factor-kappa B (NF-kappaB) expression, regulation of death genes and gene products, and differential YY1 binding in the presence of inflammatory mediators. Further, recent findings implicate YY1 in the regulation of tumor cell resistance to chemotherapeutics and immune-mediated apoptotic stimuli. Taken together, these findings provide strong support of the hypothesis that YY1, in addition to its regulatory roles in normal biologic processes, may possess the potential to act as an initiator of tumorigenesis and may thus serve as both a diagnostic and prognostic tumor marker; furthermore, it may provide an effective target for antitumor chemotherapy and/or immunotherapy. .Oncogene (2006) 25, 1125-1142. doi:10.1038/sj.onc.1209080; published online 28 November 2005.
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              The Depsipeptide Romidepsin Reverses HIV-1 Latency In Vivo

              Pharmacologically-induced activation of replication competent proviruses from latency in the presence of antiretroviral treatment (ART) has been proposed as a step towards curing HIV-1 infection. However, until now, approaches to reverse HIV-1 latency in humans have yielded mixed results. Here, we report a proof-of-concept phase Ib/IIa trial where 6 aviremic HIV-1 infected adults received intravenous 5 mg/m2 romidepsin (Celgene) once weekly for 3 weeks while maintaining ART. Lymphocyte histone H3 acetylation, a cellular measure of the pharmacodynamic response to romidepsin, increased rapidly (maximum fold range: 3.7–7.7 relative to baseline) within the first hours following each romidepsin administration. Concurrently, HIV-1 transcription quantified as copies of cell-associated un-spliced HIV-1 RNA increased significantly from baseline during treatment (range of fold-increase: 2.4–5.0; p = 0.03). Plasma HIV-1 RNA increased from <20 copies/mL at baseline to readily quantifiable levels at multiple post-infusion time-points in 5 of 6 patients (range 46–103 copies/mL following the second infusion, p = 0.04). Importantly, romidepsin did not decrease the number of HIV-specific T cells or inhibit T cell cytokine production. Adverse events (all grade 1–2) were consistent with the known side effects of romidepsin. In conclusion, romidepsin safely induced HIV-1 transcription resulting in plasma HIV-1 RNA that was readily detected with standard commercial assays demonstrating that significant reversal of HIV-1 latency in vivo is possible without blunting T cell-mediated immune responses. These finding have major implications for future trials aiming to eradicate the HIV-1 reservoir. Trial Registration clinicaltrials.gov NTC02092116
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                Author and article information

                Contributors
                zeina.nehmeh1@hotmail.com
                sebastien.pasquereau@univ-fcomte.fr
                +33-381-665-552 , georges.herbein@univ-fcomte.fr
                Journal
                Clin Epigenetics
                Clin Epigenetics
                Clinical Epigenetics
                BioMed Central (London )
                1868-7075
                1868-7083
                27 March 2019
                27 March 2019
                2019
                : 11
                : 55
                Affiliations
                [1 ]ISNI 0000 0001 2188 3779, GRID grid.7459.f, Department Pathogens & Inflammation-EPILAB, UPRES EA4266, , University of Franche-Comté, University of Bourgogne Franche-Comté, ; 16 route de Gray, F-25030 Besançon cedex, France
                [2 ]ISNI 0000 0001 2324 3572, GRID grid.411324.1, Université Libanaise, ; Beirut, Lebanon
                [3 ]ISNI 0000 0004 0638 9213, GRID grid.411158.8, Department of Virology, , CHRU Besancon, ; F-25030 Besançon, France
                Article
                654
                10.1186/s13148-019-0654-9
                6437953
                30917875
                97642799-ed87-4ad6-89e7-ff89ef38d53a
                © The Author(s). 2019

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

                History
                : 20 November 2018
                : 13 March 2019
                Funding
                Funded by: Université de Franche-Comte
                Award ID: CR 3300
                Award Recipient :
                Funded by: Municipality of Habbouch
                Categories
                Review
                Custom metadata
                © The Author(s) 2019

                Genetics
                virus,hiv,hcmv,epigenetics,treatment,cancer
                Genetics
                virus, hiv, hcmv, epigenetics, treatment, cancer

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