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Review
. 2013 May 23;5(5):1325-45.
doi: 10.3390/v5051325.

Epigenetic control of cytomegalovirus latency and reactivation

Xue-feng Liu  1 , Xueqiong Wang, Shixian Yan, Zheng Zhang, Michael Abecassis, Mary Hummel
Affiliations
Review

Epigenetic control of cytomegalovirus latency and reactivation

Xue-feng Liu et al. Viruses. .

Abstract

Cytomegalovirus (CMV) gene expression is repressed in latency due to heterochromatinization of viral genomes. In murine CMV (MCMV) latently infected mice, viral genomes are bound to histones with heterochromatic modifications, to enzymes that mediate these modifications, and to adaptor proteins that may recruit co-repressor complexes. Kinetic analyses of repressor binding show that these repressors are recruited at the earliest time of infection, suggesting that latency may be the default state. Kidney transplantation leads to epigenetic reprogramming of latent viral chromatin and reactivation of immediate early gene expression. Inflammatory signaling pathways, which activate transcription factors that regulate the major immediate early promoter (MIEP), likely mediate the switch in viral chromatin.

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Figures

Figure 1
Figure 1
(A) Chromatin immunoprecipitation analysis of binding of RNA polymerase II and HDAC2 to the murine cytomegalovirus (MCMV) major immediate early promoter (MIEP) over the course of infection [32]. Results similar to those of HDAC2 were observed for binding of other repressors, including HDAC3, YY1, Rbpj, CIR, and Daxx. *, p < 0.05 relative to Day 7. Copyright © 2010, American Society for Microbiology; (B) Model for establishment of MCMV latency. Viral DNA is not complexed with histones in the virion, but is rapidly heterochromatinized upon entry in the nucleus. Co-repressor complexes may be recruited to MCMV DNA through interaction with transcription factors that bind directly to sequences in the viral genome, including YY1 and Rbpj/CBF-1. We speculate that loss of repressors in MCMV infection is due to inactivation of host cell defenses by viral proteins analogous to the HCMV pp71 tegument protein [77]. Activation of viral gene expression may fail to occur in some cells, and these cells may be the reservoir for latency. Reproduced with permission from [11].
Figure 2
Figure 2
Chromatin immunoprecipitation analysis of epigenomic changes in the ie region induced by allogeneic transplantation. Due to the low copy number, chromatin from 30 mice was pooled for analysis of MCMV DNA in latent and transplanted kidneys. ChIP assays were analyzed in triplicate as previously described [31,32]. Results shown are the mean percent input plus standard deviation (A and B) or the ratio of modified histone to total histone after normalization to input DNA (C–E). Ratios are greater than one due to differences in antibody affinity. These results are representative of two experiments. A, acutely infected kidney; L, latently infected kidney; T, transplanted kidney; afp, alpha-fetoprotein.
Figure 3
Figure 3
Model for reactivation of CMV from latency. In latently infected cells, episomal viral genomes are heterochromatinized, and transcription factors that drive IE gene expression, such as NF-κB and AP-1, are inactive (NF-κB depicted as cytoplasmic trimeric complex of p65, p50, and the inhibitory subunit, IκB). We propose that inflammatory cytokines and oxidative stress lead to activation of transcription factors that bind to the MIEP and induce chromatin remodeling to activate ie gene expression. Reactivation of ie gene expression does not lead to reactivation of virus in immunocompetent individuals, but in immunosuppressed individuals, reactivation of IE gene expression leads to production of infectious virus.
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References

    1. Britt W. Manifestations of human cytomegalovirus infection: Proposed mechanisms of acute and chronic disease. Curr. Top. Microbiol. Immunol. 2008;325:417–470. doi: 10.1007/978-3-540-77349-8_23. - DOI - PubMed
    1. Freeman R.B. The ‘indirect’ effects of cytomegalovirus infection. Am. J. Transplant. 2009;9:2453–2458. doi: 10.1111/j.1600-6143.2009.02824.x. - DOI - PubMed
    1. Fishman J.A., Emery V., Freeman R., Pascual M., Rostaing L., Schlitt H.J., Sgarabotto D., Torre-Cisneros J., Uknis M.E. Cytomegalovirus in transplantation—Challenging the status quo. Clin. Transplant. 2007;21:149–158. doi: 10.1111/j.1399-0012.2006.00618.x. - DOI - PubMed
    1. Singh N. Late-onset cytomegalovirus disease as a significant complication in solid organ transplant recipients receiving antiviral prophylaxis: A call to heed the mounting evidence. Clin. Infect. Dis. 2005;40:704–708. doi: 10.1086/427506. - DOI - PubMed
    1. Pereira L., Maidji E. Cytomegalovirus infection in the human placenta: Maternal immunity and developmentally regulated receptors on trophoblasts converge. Curr. Top. Microbiol. Immunol. 2008;325:383–395. doi: 10.1007/978-3-540-77349-8_21. - DOI - PubMed

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