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Updated: Jun 12, 2025
Dissecting Innate Immune Signaling in Viral Evasion of Cytokine Production
Published on: March 2, 2014
The Pentamer glycoprotein complex inhibits viral Immediate Early transcription during Human Cytomegalovirus
Michael S Ohman1, Emily R Albright1, Christopher B Gelbmann1
1Institute for Molecular Virology and McArdle Laboratory for Cancer Research, University of Wisconsin-Madison, Madison, WI 53706.
Abstract:
The Pentamer complex of Human Cytomegalovirus (HCMV) consists of the viral glycoproteins gH, gL, UL128, UL130, and UL131 and is incorporated into infectious virions. HCMV strains propagated extensively in vitro in fibroblasts carry UL128, UL130, or UL131 alleles that do not make a functional complex and thus lack Pentamer function. Adding functional Pentamer to such strains decreases virus growth in fibroblasts. Here, we show that the Pentamer inhibits productive HCMV replication in fibroblasts by repressing viral Immediate Early (IE) transcription. We show that ectopic expression of the viral IE1 protein, a target of Pentamer-mediated transcriptional repression, complements the growth defect of a Pentamer-positive virus. Furthermore, we show that the Pentamer also represses viral IE transcription in cell types where HCMV in vitro latency is studied. Finally, we identify UL130 as a functional subunit of the Pentamer for IE transcriptional repression and demonstrate that cyclic AMP Response Element (CRE) and NFkB sites within the Major Immediate Early Promoter that drives IE1 transcription contribute to this repression. We conclude that the HCMV Pentamer represses viral IE transcription.
Insights
The Human Cytomegalovirus (HCMV) Pentamer complex inhibits virus replication by repressing viral Immediate Early (IE) transcription. This finding reveals a new mechanism for controlling HCMV infection in fibroblasts and during latency.
Area of Science:
- Virology
- Molecular Biology
- Immunology
Background:
- The Pentamer complex, comprising gH, gL, UL128, UL130, and UL131, is crucial for Human Cytomegalovirus (HCMV) infectivity.
- HCMV strains propagated in vitro often lack a functional Pentamer complex due to defective UL128, UL130, or UL131 alleles.
- Introduction of functional Pentamer into such strains can impede virus growth in fibroblasts.
Purpose of the Study:
- To investigate the mechanism by which the HCMV Pentamer complex influences viral replication in fibroblasts.
- To determine the role of the Pentamer complex in regulating viral gene expression, specifically Immediate Early (IE) transcription.
- To identify the specific Pentamer subunit and promoter elements involved in transcriptional repression.
Main Methods:
- Analysis of HCMV replication in fibroblasts with and without functional Pentamer complex.
- Assessment of viral Immediate Early (IE) gene transcription using various assays.
- Complementation studies involving ectopic expression of the IE1 protein.
- Identification of functional Pentamer subunits and analysis of promoter elements (CRE, NFkB) in IE gene regulation.
Main Results:
- The HCMV Pentamer complex was found to inhibit productive HCMV replication in fibroblasts.
- This inhibition was mediated by the repression of viral Immediate Early (IE) transcription.
- Ectopic expression of the IE1 protein rescued the growth defect of Pentamer-positive HCMV.
- The Pentamer complex also repressed viral IE transcription in cell types relevant to HCMV latency.
- UL130 was identified as a key subunit for IE transcriptional repression, involving CRE and NFkB sites in the Major Immediate Early Promoter.
Conclusions:
- The HCMV Pentamer complex actively represses viral Immediate Early (IE) transcription.
- This repression mechanism contributes to the regulation of HCMV replication in fibroblasts.
- The findings elucidate a novel role for the Pentamer complex in controlling viral gene expression and replication, with implications for understanding HCMV latency.
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