Interferon-Responsive Genes Are Targeted during the Establishment of Human Cytomegalovirus Latency

Elder, Elizabeth; Krishna, Benjamin A.; Williamson, James C; Lim, Eleanor; Poole, Emma; Sedikides, George X.; Wills, Mark R.; O’Connor, Christine M.; Lehner, Paul J.; Sinclair, John

doi:10.1128/mbio.02574-19

Cited by 34 publications

(42 citation statements)

References 86 publications

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“…More recently, cellular proteins that mediate foreign or damaged DNA sensing and signalling, including cyclic guanosine monophosphate-adenosine monophosphate (cGAMP) synthase, interferon (IFN) gamma-inducible protein 16 (IFI16) and stimulator of IFN genes (STING), have been identified as restriction factors of HCMV and other DNA viruses [139][140][141][142]. These proteins are known or predicted to restrict IE transcription, at least indirectly, although IFI16 may activate rather than repress the MIEP [143,144].…”

Section: Transcriptional Control Of the Major Ie Genementioning

confidence: 99%

Bright and Early: Inhibiting Human Cytomegalovirus by Targeting Major Immediate-Early Gene Expression or Protein Function

Adamson

Nevels

2020

Viruses

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The human cytomegalovirus (HCMV), one of eight human herpesviruses, establishes lifelong latent infections in most people worldwide. Primary or reactivated HCMV infections cause severe disease in immunosuppressed patients and congenital defects in children. There is no vaccine for HCMV, and the currently approved antivirals come with major limitations. Most approved HCMV antivirals target late molecular processes in the viral replication cycle including DNA replication and packaging. “Bright and early” events in HCMV infection have not been exploited for systemic prevention or treatment of disease. Initiation of HCMV replication depends on transcription from the viral major immediate-early (IE) gene. Alternative transcripts produced from this gene give rise to the IE1 and IE2 families of viral proteins, which localize to the host cell nucleus. The IE1 and IE2 proteins are believed to control all subsequent early and late events in HCMV replication, including reactivation from latency, in part by antagonizing intrinsic and innate immune responses. Here we provide an update on the regulation of major IE gene expression and the functions of IE1 and IE2 proteins. We will relate this insight to experimental approaches that target IE gene expression or protein function via molecular gene silencing and editing or small chemical inhibitors.

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Section: Transcriptional Control Of the Major Ie Genementioning

confidence: 99%

Bright and Early: Inhibiting Human Cytomegalovirus by Targeting Major Immediate-Early Gene Expression or Protein Function

Adamson

Nevels

2020

Viruses

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“…However, while immediate early (IE) gene expression is suppressed during latency, other viral genes are expressed [7,[13][14][15][16][17][18], suggesting that latency is distinct from viral quiescence. Indeed, several latency-associated gene products have been ascribed functions during HCMV latency, including immune evasion [19][20][21], PML body dispersion [22], and modulation of key cellular signalling pathways in order to suppress IE gene expression [12,[23][24][25][26][27].…”

Section: Introductionmentioning

confidence: 99%

Regulation of host and viral promoters during human cytomegalovirus latency via US28 and CTCF

Krishna

Poole

Perera

2021

Journal of General Virology

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Viral latency is an active process during which the host cell environment is optimized for latent carriage and reactivation. This requires control of both viral and host gene promoters and enhancers often at the level of chromatin, and several viruses co-opt the chromatin organiser CTCF to control gene expression during latency. While CTCF has a role in the latencies of alpha- and gamma-herpesviruses, it was not known whether CTCF played a role in the latency of the beta-herpesvirus human cytomegalovirus (HCMV). Here, we show that HCMV latency is associated with increased CTCF expression and CTCF binding to the viral major lytic promoter, the major immediate early promoter (MIEP). This increase in CTCF binding is dependent on the virally encoded G protein coupled receptor, US28, and contributes to suppression of MIEP-driven transcription, a hallmark of latency. Furthermore, we show that latency-associated upregulation of CTCF represses expression of the neutrophil chemoattractants S100A8 and S100A9 which we have previously shown are downregulated during HCMV latency. As with downregulation of the MIEP, CTCF binding to the enhancer region of S100A8/A9 drives their suppression, again in a US28-dependent manner. Taken together, we identify CTCF upregulation as an important mechanism for optimizing latent carriage of HCMV at both the levels of viral and cellular gene expression.

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“…Type 1 interferon (IFN) response upregulates PML-associated host factors and reversibly blocks IE gene expression to drive latency in MCMV-infected endothelial cells (Dag et al, 2014). In the context of HCMV infection, US28-mediated downregulation of IFN responsive genes is required for latency and IFI16 stimulates IE gene expression via NFkB for reactivation (Elder et al, 2019). In HSV-1 infection, IFI16 restricts HSV-1 gene expression and is targeted by ICP0 for destruction to stimulate gene expression (Orzalli et al, 2012;Merkl and Knipe, 2019).…”

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confidence: 99%

Control of Immediate Early Gene Expression for Human Cytomegalovirus Reactivation

Collins-McMillen

Kamil

Moorman

et al. 2020

Front. Cell. Infect. Microbiol.

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Interferon-Responsive Genes Are Targeted during the Establishment of Human Cytomegalovirus Latency

Cited by 34 publications

References 86 publications

Bright and Early: Inhibiting Human Cytomegalovirus by Targeting Major Immediate-Early Gene Expression or Protein Function

Bright and Early: Inhibiting Human Cytomegalovirus by Targeting Major Immediate-Early Gene Expression or Protein Function

Regulation of host and viral promoters during human cytomegalovirus latency via US28 and CTCF

Control of Immediate Early Gene Expression for Human Cytomegalovirus Reactivation

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