Control of Immediate Early Gene Expression for Human Cytomegalovirus Reactivation

Collins-McMillen, Donna; Kamil, Jeremy P.; Moorman, Nathaniel J.; Goodrum, Felicia

doi:10.3389/fcimb.2020.00476

Cited by 18 publications

(18 citation statements)

References 116 publications

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“…For HCMV, this was further refined to seven temporal classes [ 50 ]. The major immediate-early genes of herpesviruses are critical trans-activators, driving acute virus replication and are thought to be pivotal in regulating viral latency [ 51 , 52 ]. HCMV expresses two major immediate-early transcripts, IE1 and IE2, which share the first three exons and are generated by alternative splicing and polyadenylation.…”

Section: Evasion Of Zap By Beta-herpesvirusesmentioning

confidence: 99%

Does the Zinc Finger Antiviral Protein (ZAP) Shape the Evolution of Herpesvirus Genomes?

Lin

Chau

Coutts

et al. 2021

Viruses

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An evolutionary arms race occurs between viruses and hosts. Hosts have developed an array of antiviral mechanisms aimed at inhibiting replication and spread of viruses, reducing their fitness, and ultimately minimising pathogenic effects. In turn, viruses have evolved sophisticated counter-measures that mediate evasion of host defence mechanisms. A key aspect of host defences is the ability to differentiate between self and non-self. Previous studies have demonstrated significant suppression of CpG and UpA dinucleotide frequencies in the coding regions of RNA and small DNA viruses. Artificially increasing these dinucleotide frequencies results in a substantial attenuation of virus replication, suggesting dinucleotide bias could facilitate recognition of non-self RNA. The interferon-inducible gene, zinc finger antiviral protein (ZAP) is the host factor responsible for sensing CpG dinucleotides in viral RNA and restricting RNA viruses through direct binding and degradation of the target RNA. Herpesviruses are large DNA viruses that comprise three subfamilies, alpha, beta and gamma, which display divergent CpG dinucleotide patterns within their genomes. ZAP has recently been shown to act as a host restriction factor against human cytomegalovirus (HCMV), a beta-herpesvirus, which in turn evades ZAP detection by suppressing CpG levels in the major immediate-early transcript IE1, one of the first genes expressed by the virus. While suppression of CpG dinucleotides allows evasion of ZAP targeting, synonymous changes in nucleotide composition that cause genome biases, such as low GC content, can cause inefficient gene expression, especially in unspliced transcripts. To maintain compact genomes, the majority of herpesvirus transcripts are unspliced. Here we discuss how the conflicting pressures of ZAP evasion, the need to maintain compact genomes through the use of unspliced transcripts and maintaining efficient gene expression may have shaped the evolution of herpesvirus genomes, leading to characteristic CpG dinucleotide patterns.

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Section: Evasion Of Zap By Beta-herpesvirusesmentioning

confidence: 99%

Does the Zinc Finger Antiviral Protein (ZAP) Shape the Evolution of Herpesvirus Genomes?

Lin

Chau

Coutts

et al. 2021

Viruses

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“…Several CMV genes (US2, US3, US6, and US11) interfere with cell-mediated immune responses or encode immunomodulatory gene products that can play a role in CMV immune evasion and favour latency. While much remains to be understood about the signalling events and coordination of repressive activities to repress viral gene expression for latency, much less is known about how these layers of control are unravelled for reactivation [ 26 ]. Presently, it is thought that reactivation is strictly linked with the expression of two major early proteins, IE72 and IE76, and with the presence of LUNA, UL138, US28, and LAcmvIL-10 [ 27 ].…”

Section: Immune Response Of the Host To CMV Infectionmentioning

confidence: 99%

Prevention of Congenital Cytomegalovirus Infection with Vaccines: State of the Art

et al. 2021

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Cytomegalovirus (CMV) is the most common cause of congenital infection and non-genetic sensorineural hearing loss in childhood. Up to 2% of neonates, with the highest percentages found in developing countries, are congenitally infected with CMV. At birth, most of these infants are asymptomatic. However, approximately 10% have signs and symptoms of the disease, and 40–60% of symptomatic neonates will later develop permanent neurologic sequelae. To reduce congenital CMV (cCMV) infection, a vaccine able to prevent primary infection is essential. In this narrative review, actual ongoing research about the development of a CMV vaccine is discussed. The progressive increase in knowledge on the ways in which the host’s immune system and CMV relate has made it possible to clarify that the development of a vaccine that is certainly capable of reducing the risk of cCMV infection, and preventing both primary and nonprimary infections is extremely difficult. Many of the ways in which the virus evades the immune system and causes cCMV infection are not yet fully understood, especially in cases of nonprimary infection. Moreover, the schedule that should be recommended and that subjects must be vaccinated to obtain the greatest effect have not been precisely defined. Further studies are needed before the problem of cCMV infection and its related challenges can be totally solved.

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Section: Introductionmentioning

confidence: 99%

“…The complex processes involved in virion production from latent-to-lytic switch are sequentially coordinated by the expression of major immediate-early (MIE), early, and late genes [ 5 , 13 , 14 , 15 ]. The expression of immediate-early (IE) proteins (IE72 encoded by UL123 and IE86 encoded by UL122 ) immediately after chromatin-mediated epigenetic remodeling of the HCMV DNA is essential for the transcription of early and late genes [ 5 , 13 , 14 , 15 , 16 , 17 , 18 ]. While the robust activation of the MIE gene initiates significantly productive HCMV replication, the absence or low levels of IE proteins are directly connected to the establishment of latency in undifferentiated CD34 + hematopoietic progenitor cells (HPCs) [ 12 , 13 , 19 , 20 ].…”

Section: Introductionmentioning

confidence: 99%

“…While the robust activation of the MIE gene initiates significantly productive HCMV replication, the absence or low levels of IE proteins are directly connected to the establishment of latency in undifferentiated CD34 + hematopoietic progenitor cells (HPCs) [ 12 , 13 , 19 , 20 ]. Therefore, the sustained downregulation of IEs might be a key element in maintaining latency and preventing the development of a wide range of diseases [ 13 , 15 , 21 , 22 , 23 ].…”

Section: Introductionmentioning

confidence: 99%

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Human MicroRNAs Attenuate the Expression of Immediate Early Proteins and HCMV Replication during Lytic and Latent Infection in Connection with Enhancement of Phosphorylated RelA/p65 (Serine 536) That Binds to MIEP

Hong

Min

Kim

et al. 2022

IJMS

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Attenuating the expression of immediate early (IE) proteins is essential for controlling the lytic replication of human cytomegalovirus (HCMV). The human microRNAs (hsa-miRs), miR-200b-3p and miR-200c-3p, have been identified to bind the 3′-untranslated region (3′-UTR) of the mRNA encoding IE proteins. However, whether hsa-miRs can reduce IE72 expression and HCMV viral load or exhibit a crosstalk with the host cellular signaling machinery, most importantly the NF-κB cascade, has not been evaluated. In this study, argonaute-crosslinking and immunoprecipitation-seq revealed that miR-200b-3p and miR-200c-3p bind the 3′-UTR of UL123, which is a gene that encodes IE72. The binding of these miRNAs to the 3′-UTR of UL123 was verified in transfected cells stably expressing GFP. We used miR-200b-3p/miR-200c-3p mimics to counteract the downregulation of these miRNA after acute HCMV infection. This resulted in reduced IE72/IE86 expression and HCMV VL during lytic infection. We determined that IE72/IE86 alone can inhibit the phosphorylation of RelA/p65 at the Ser536 residue and that p-Ser536 RelA/p65 binds to the major IE promoter/enhancer (MIEP). The upregulation of miR-200b-3p and miR-200c-3p resulted in the phosphorylation of RelA/p65 at Ser536 through the downregulation of IE, and the binding of the resultant p-Ser536 RelA/p65 to MIEP resulted in a decreased production of pro-inflammatory cytokines. Overall, miR-200b-3p and miR-200c-3p—together with p-Ser536 RelA/p65—can prevent lytic HCMV replication during acute and latent infection.

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Control of Immediate Early Gene Expression for Human Cytomegalovirus Reactivation

Cited by 18 publications

References 116 publications

Does the Zinc Finger Antiviral Protein (ZAP) Shape the Evolution of Herpesvirus Genomes?

Does the Zinc Finger Antiviral Protein (ZAP) Shape the Evolution of Herpesvirus Genomes?

Prevention of Congenital Cytomegalovirus Infection with Vaccines: State of the Art

Human MicroRNAs Attenuate the Expression of Immediate Early Proteins and HCMV Replication during Lytic and Latent Infection in Connection with Enhancement of Phosphorylated RelA/p65 (Serine 536) That Binds to MIEP

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