The power of human cytomegalovirus (HCMV) hijacked UL/b' functions lost in vitro

Kempová, V; Lenhartová, Simona; Benko, Mário; Nemčovič, Marek; Kúdelová, M; Nemčovičová, Ivana

doi:10.4149/av_2020_202

Cited by 5 publications

(10 citation statements)

References 108 publications

(141 reference statements)

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“…The ULb' region is present in low-passage strains and clinical isolates but lost during serial passage of the virus in fibroblasts, thus partly or entirely lacking in most laboratoryadapted strains. While dispensable for replication in fibroblasts, these genes undoubtedly play important roles in other contexts of infection in the host (34)(35)(36)(37). We have characterized a 3.6-kb polycistronic gene locus within the ULb' region encoding four genes, UL133, UL135, UL136, and UL138, collectively referred to as the UL133-UL138 locus (19,38).…”

Section: Introductionmentioning

confidence: 99%

UL135 and UL136 Epistasis Controls Reactivation of Human Cytomegalovirus

Moy

Collins-McMillen

Crawford

et al. 2023

Preprint

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Human cytomegalovirus (HCMV) is beta herpesvirus that persists indefinitely in the human host through a protracted, latent infection. The polycistronic UL133-UL138 gene locus of HCMV encodes genes regulating latency and reactivation. While UL138 is pro-latency, restricting virus replication in CD34+ hematopoietic progenitor cells (HPCs), UL135 overcomes this restriction for reactivation. By contrast, UL136 is expressed with later kinetics and encodes multiple protein isoforms with differential roles in latency and reactivation. Like UL135, the largest UL136 isoform, UL136p33, is required for reactivation from latency in hematopoietic cells. Furthermore, UL136p33 is unstable, and its instability is important for the establishment of latency and sufficient accumulation of UL136p33 is a checkpoint for reactivation. We hypothesized that stabilizing UL136p33 might overcome the requirement of UL135 for reactivation. To test this, we generated recombinant viruses lacking UL135 that expressed a stabilized variant of UL136p33. Stabilizing UL136p33 did not impact replication of the UL135-mutant virus in fibroblasts. However, in the context of infection in hematopoietic cells, stabilization of UL136p33 strikingly compensated for the loss of UL135, resulting in increased replication in CD34+ HPCs and in humanized NOD-scid IL2Rgammacnull (NSG) mice. This finding suggests that while UL135 is essential for reactivation, it functions at steps preceding the accumulation of UL136p33 and that stabilized expression of UL136p33 largely overcomes the requirement for UL135 in reactivation. Taken together, our genetic evidence indicates an epistatic relationship between UL136p33 and UL135 whereby UL135 may initiate events early in reactivation that will result in the accumulation of UL136p33 to a threshold required for productive reactivation.

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Section: Introductionmentioning

confidence: 99%

UL135 and UL136 Epistasis Controls Reactivation of Human Cytomegalovirus

Moy

Collins-McMillen

Crawford

et al. 2023

Preprint

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“…We chose the UL133-UL138-missing backbone as one part of the rationale for our studies. The deletion of the genomic region UL133-UL138 in the chosen virus context is linked to an increased dependence of the virus on pUL97 kinase activity [ 17 , 18 , 19 , 20 ]. For reasons of a complex regulatory interference between the viral proteins that normally are expressed by this genomic region (e.g., the early regulators of ORF-UL138 proteins and others) with the pUL97 functionality, such an HCMV strain, and mutants derived from it, are expected to be particularly sensitive to any regulatory or drug-mediated impairment of pUL97.…”

Section: Methodsmentioning

confidence: 99%

Recombinant Human Cytomegalovirus Expressing an Analog-Sensitive Kinase pUL97 as Novel Tool for Functional Analyses

Krämer¹,

Schütz

Mato

et al. 2022

Viruses

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The human cytomegalovirus (HCMV) is a member of the beta-herpesvirus family and inflicts life-long latent infections in its hosts. HCMV has been shown to manipulate and dysregulate many cellular processes. One major interactor with the cellular host is the viral kinase pUL97. The UL97 gene is essential for viral replication, and kinase-deficient mutants of pUL97 display a severe replication defect. Recently, another group established an analog-sensitive version of the pUL97 protein. This mutant kinase can be treated with a non-hydrolysable ATP analog, thereby inhibiting its kinase function. This process is reversible by removing the ATP analog by media change. We introduced this mutant version of the pUL97 protein into the laboratory strain Ad169 of HCMV, BADwt, creating a BAD-UL97-as1 viral mutant. This mutant virus replicated normally in infected cells in the absence of the ATP analog and maintained its ability to phosphorylate its cellular substrates. However, when treated with the ATP analog, BAD-UL97-as1 displayed a defect in the production of intra- and extracellular viral DNA and in the production of viral progeny. Furthermore, in the presence of 3MB-PP1, a well-established substrate of pUL97 was no longer hyperphosphorylated. This effect was detectable as early as 4 h post treatment, which allows for studies on pUL97 without the complication of low viral titers. Nevertheless, we observed off-target effects of 3MB-PP1 on several cellular processes, which should be considered with this approach.

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“…Chemokine analogue [373]; Induces cell PBMC proliferation and inflammation [32,374,375]; Viral entry and assembly, regulation of actin cytoskeleton [376]; Triggers monocyte paralysis, monocyte infection, blocks migration [377]; gH/gL/UL128-131 complex, promotes entry into cells, broadens virus tropism [214,378,379] Cell proliferation, Induces inflammation [374] Cell migration [377] Cell tropism [380] UL129 Unknown Unknown…”

Section: Ul128mentioning

confidence: 99%

“…Viral entry and assembly [376]; gH/gL/UL128-131 complex, promotes entry into cells, broadens virus tropism [214,378,379]; pUL130 and Snapin interact to modulate DNA synthesis [381];…”

Section: Ul130mentioning

confidence: 99%

Insights into the Transcriptome of Human Cytomegalovirus: A Comprehensive Review

Zeng

Cao

Yang

et al. 2023

Viruses

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Human cytomegalovirus (HCMV) is a widespread pathogen that poses significant risks to immunocompromised individuals. Its genome spans over 230 kbp and potentially encodes over 200 open-reading frames. The HCMV transcriptome consists of various types of RNAs, including messenger RNAs (mRNAs), long non-coding RNAs (lncRNAs), circular RNAs (circRNAs), and microRNAs (miRNAs), with emerging insights into their biological functions. HCMV mRNAs are involved in crucial viral processes, such as viral replication, transcription, and translation regulation, as well as immune modulation and other effects on host cells. Additionally, four lncRNAs (RNA1.2, RNA2.7, RNA4.9, and RNA5.0) have been identified in HCMV, which play important roles in lytic replication like bypassing acute antiviral responses, promoting cell movement and viral spread, and maintaining HCMV latency. CircRNAs have gained attention for their important and diverse biological functions, including association with different diseases, acting as microRNA sponges, regulating parental gene expression, and serving as translation templates. Remarkably, HCMV encodes miRNAs which play critical roles in silencing human genes and other functions. This review gives an overview of human cytomegalovirus and current research on the HCMV transcriptome during lytic and latent infection.

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The power of human cytomegalovirus (HCMV) hijacked UL/b' functions lost in vitro

Cited by 5 publications

References 108 publications

UL135 and UL136 Epistasis Controls Reactivation of Human Cytomegalovirus

UL135 and UL136 Epistasis Controls Reactivation of Human Cytomegalovirus

Recombinant Human Cytomegalovirus Expressing an Analog-Sensitive Kinase pUL97 as Novel Tool for Functional Analyses

Insights into the Transcriptome of Human Cytomegalovirus: A Comprehensive Review

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