The Transcriptome of Latent Human Cytomegalovirus

Schwartz, Michal; Stern-Ginossar, Noam

doi:10.1128/jvi.00047-19

Cited by 31 publications

(20 citation statements)

References 47 publications

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“…Finally, late genes are expressed after viral DNA replication has commenced and encode mostly structural proteins of the capsid, tegument or envelope required for the assembly and egress of progeny virions [19][20][21]. HCMV replicates in a wide variety of differentiated cell types, and targets select types of poorly differentiated cells including myeloid progenitors for latent infection with limited viral gene expression [22][23][24][25][26]. Viral reactivation from latency is brought about by cellular differentiation and/or stimulation and contributes greatly to pathogenesis in vulnerable hosts [27][28][29].…”

Section: Introductionmentioning

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: Introductionmentioning

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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“…HCMV can establish lytic or latent infection in different cell lines (Schwartz and Stern-Ginossar, 2019). THP-1 macrophages are usually used as an HCMV experimental lytic infection model (Sanchez et al, 2012).…”

Section: Discussionmentioning

confidence: 99%

Association of TRIM22 with the type 1 interferon response during primary human cytomegalovirus infection in THP-1 macrophages

Li¹,

Gao²,

Tao³

et al. 2019

Biocell

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As a response factor of interferon, tripartite motif (TRIM) 22 was reported to exert antiviral activity against viruses. In this study, THP-1 macrophages were infected with human cytomegalovirus (HCMV) to establish the HCMV lytic infection model. The mRNA levels of interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α) and interferonbeta (IFN-β) were significantly up-regulated in THP-1 macrophages at different infection time and titers. Moreover, for the first time, upregulation of TRIM22 expression was found during HCMV infection at both mRNA and protein levels in THP-1 macrophages. Furthermore, IFN-β could induce TRIM22 expression in THP-1 macrophages or HCMV infected THP-1 macrophages. Depletion of TRIM22 increased replication activity of HCMV with increasing of HCMV titers and HCMV proteins. In conclusion, it is the first report that HCMV can induce TRIM22 activation through IFN-β signaling and TRIM22 can suppress replication of HCMV in THP-1 macrophages.

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“…Recent studies of viral gene expression have taken advantage of the development of sensitive, high throughput, and unbiased analyses to interrogate the latent viral transcriptome in both naturally and experimentally infected myeloid cells (Rossetto et al, 2013;Cheng et al, 2017;Shnayder et al, 2018;Schwartz and Stern-Ginossar, 2019). In contrast to earlier reports, these studies detected expression of many lytic genes, and did not find evidence for a latency-specific transcriptional profile.…”

Section: Latency: Are There Latency-specific Transcripts?mentioning

confidence: 93%

“…Single cell analysis of experimentally infected monocytes has shed some light on this paradox (Shnayder et al, 2018(Shnayder et al, , 2020Schwartz and Stern-Ginossar, 2019). This study revealed that there is marked heterogeneity in the cellular response to infection.…”

Section: Latency: Are There Latency-specific Transcripts?mentioning

confidence: 98%

Cytomegalovirus Latency and Reactivation: An Intricate Interplay With the Host Immune Response

Forte

Zhang

Thorp

et al. 2020

Front. Cell. Infect. Microbiol.

137

103

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CMV is an ancient herpesvirus that has co-evolved with its host over millions of years. The 236 kbp genome encodes at least 165 genes, four non-coding RNAs and 14 miRNAs. Of the protein-coding genes, 43-44 are core replication genes common to all herpesviruses, while ∼30 are unique to betaherpesviruses. Many CMV genes are involved in evading detection by the host immune response, and others have roles in cell tropism. CMV replicates systemically, and thus, has adapted to various biological niches within the host. Different biological niches may place competing demands on the virus, such that genes that are favorable in some contexts are unfavorable in others. The outcome of infection is dependent on the cell type. In fibroblasts, the virus replicates lytically to produce infectious virus. In other cell types, such as myeloid progenitor cells, there is an initial burst of lytic gene expression, which is subsequently silenced through epigenetic repression, leading to establishment of latency. Latently infected monocytes disseminate the virus to various organs. Latency is established through cell type specific mechanisms of transcriptional silencing. In contrast, reactivation is triggered through pathways activated by inflammation, infection, and injury that are common to many cell types, as well as differentiation of myeloid cells to dendritic cells. Thus, CMV has evolved a complex relationship with the host immune response, in which it exploits cell type specific mechanisms of gene regulation to establish latency and to disseminate infection systemically, and also uses the inflammatory response to infection as an early warning system which allows the virus to escape from situations in which its survival is threatened, either by cellular damage or infection of the host with another pathogen. Spontaneous reactivation induced by cellular aging/damage may explain why extensive expression of lytic genes has been observed in recent studies using highly sensitive transcriptome analyses of cells from latently infected individuals. Recent studies with animal models highlight the potential for harnessing the host immune response to blunt cellular injury induced by organ transplantation, and thus, prevent reactivation of CMV and its sequelae.

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The Transcriptome of Latent Human Cytomegalovirus

Cited by 31 publications

References 47 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

Association of TRIM22 with the type 1 interferon response during primary human cytomegalovirus infection in THP-1 macrophages

Cytomegalovirus Latency and Reactivation: An Intricate Interplay With the Host Immune Response

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