The human cytomegalovirus UL78 gene is highly conserved among clinical isolates, but is dispensable for replication in fibroblasts and a renal artery organ-culture system

Michel, Detlef; Milotic, Irena; Wagner, Markus; Vaida, Bianca; Holl, Jens; Ansorge, Ramona; Mertens, Thomas

doi:10.1099/vir.0.80436-0

Cited by 41 publications

(36 citation statements)

References 37 publications

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“…They have found substantial variation in the sequences of the many conserved ORFs. Mertens and collaborators (29) reported that although the HCMV UL78 gene was highly conserved among clinical isolates, the gene was dispensable for replication in fibroblasts and a renal artery organculture system. Ruan and coworkers (22) have reported the occurrence of sequence variation caused by frameshift mutations found in the UL143 gene in all HCMV clinical strains.…”

Section: Discussionmentioning

confidence: 99%

The DR1 and DR6 First Exons of Human Herpesvirus 6A Are Not Required for Virus Replication in Culture and Are Deleted in Virus Stocks That Replicate Well in T-Cell Lines

Borenstein

Zeigerman

Frenkel

2010

J Virol

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Section: Discussionmentioning

confidence: 99%

The DR1 and DR6 First Exons of Human Herpesvirus 6A Are Not Required for Virus Replication in Culture and Are Deleted in Virus Stocks That Replicate Well in T-Cell Lines

Borenstein

Zeigerman

Frenkel

2010

J Virol

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“…Mutational analysis has shown that HCMV pUL78 is not required for normal viral growth in fibroblasts or in a renal artery tissue culture model (15). To investigate the possibility that the viral GPCR is needed for replication in other cell types, we generated a pUL78-deficient derivative of a clinical strain of HCMV with broad host cell tropism.…”

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confidence: 99%

Human Cytomegalovirus pUL78 G Protein-Coupled Receptor Homologue Is Required for Timely Cell Entry in Epithelial Cells but Not Fibroblasts

O’Connor

Shenk

2012

J Virol

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Human cytomegalovirus (HCMV) encodes four putative G protein-coupled receptors, including pUL78, whose rodent orthologues are known to be important for replication and spread in their hosts. To investigate the mechanism by which pUL78 contributes to viral replication and pathogenesis, we generated a derivative of the TB40/E clinical isolate of HCMV that is unable to express the receptor. Consistent with previous findings using laboratory strains of the virus, the mutant replicated normally in fibroblasts. Although laboratory strains are restricted to growth in fibroblasts, clinical isolates grow in many cell types, including epithelial and endothelial cells, in which the pUL78-deficient TB40/E derivative exhibited a growth defect. Infection with the mutant virus resulted in a significant decrease in viral RNA and protein expression. Although there was no difference in binding of the virus to the cell, we detected a delay in the entry and subsequent delivery of virion DNA and protein to the nuclei of epithelial cells following infection with the UL78 mutant virus. Taken together, our results demonstrate that pUL78 supports infection at a point after binding but before entry in epithelial cells, a cell type important for in vivo viral replication and spread.

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“…Previous studies on herpesvirus 7-transmembrane (7-tm) receptors have generally concluded that these genes are dispensable for in vitro replication of virus; examples include HCMV US28 (52), HCMV UL33 (30), mouse CMV (MCMV) M33 (15), rat CMV (RCMV) R33 (6), and HCMV UL78 (32). However, deletion of the MCMV M78 gene has been shown to reduce virus replication in cultured fibroblasts (37), and deletion of the RCMV R78 gene also results in attenuation of virus production in cell culture systems (5,28).…”

Section: Discussionmentioning

confidence: 99%

The Human Herpesvirus 6 G Protein-Coupled Receptor Homolog U51 Positively Regulates Virus Replication and Enhances Cell-Cell Fusion In Vitro

Zhu¹,

Bradel-Tretheway²,

Sumagin³

et al. 2005

J Virol

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Human herpesvirus 6 (HHV-6) is a ubiquitous T-lymphotropic betaherpesvirus that encodes two G proteincoupled receptor homologs, U12 and U51. HHV-6A U51 has been reported to bind to CC chemokines including RANTES, but the biological function of U51 remains uncertain. In this report, we stably expressed short interfering RNAs (siRNAs) specific for U51 in human T cells and then infected these cells with HHV-6. Viral DNA replication was reduced 50-fold by the U51 siRNA, and virally induced cytopathic effects were also inhibited. In contrast, viral replication and syncytium formation were unaltered in cells that expressed a scrambled derivative of the siRNA or an irrelevant siRNA and were restored to normal when a human codon-optimized derivative of U51 was introduced into cells containing the U51 siRNA. To examine the mechanism whereby U51 might contribute to viral replication, we explored the signaling characteristics of U51. None of the chemokines and opioids tested was able to induce G protein coupling by U51, and no evidence for opioid ligand binding by U51 was obtained. The effect of U51 on cell-cell fusion was also evaluated; these studies showed that U51 enhanced cell fusion mediated by the G protein of vesicular stomatitis virus. However, a U51-specific antiserum had no virus-neutralizing activity, suggesting that U51 may not be involved in the initial interaction between the virus particle and host cell. Overall, these studies suggest that HHV-6 U51 is a positive regulator of virus replication in vitro, perhaps because it may promote membrane fusion and facilitates cell-cell spread of this highly cell-associated virus.Human herpesvirus 6 (HHV-6) was first isolated in 1986 from patients with lymphoproliferative disorders (43) and later was identified as the causative agent of roseola infantum (56) and of acute febrile illness (41, 58) in young children. Following primary infection, the virus is able to establish a highly successful state of coexistence with the host, resulting in persistent infection with occasional but generally nonsymptomatic reactivation (13,24). However, the virus can cause rare, serious complications in immunocompromised hosts or in the context of stem cell transplantation, including encephalitis, hepatitis, and bone marrow suppression (14,54,57). There are two variants of this virus, 6A and 6B, which have characteristic differences in their cell tropism and biological properties (1, 4, 16, 44) as well as approximately 10% overall sequence divergence at the genomic level (18,23,25).The U51 gene is one of the two 7-transmembrane (7-tm) receptors carried by HHV-6 (23). It has been shown to be most closely related to the UL78 gene family from human cytomegalovirus (CMV), and gene knockout experiments using the rat CMV have revealed that this gene (R78) is necessary for efficient virus replication in vivo, suggesting that R78 (and perhaps U51 as well) may play a role in virus replication and virulence (6). Direct analyses of U51 itself have revealed that HHV-6 U51 can bind certain CC chemok...

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The human cytomegalovirus UL78 gene is highly conserved among clinical isolates, but is dispensable for replication in fibroblasts and a renal artery organ-culture system

Cited by 41 publications

References 37 publications

The DR1 and DR6 First Exons of Human Herpesvirus 6A Are Not Required for Virus Replication in Culture and Are Deleted in Virus Stocks That Replicate Well in T-Cell Lines

The DR1 and DR6 First Exons of Human Herpesvirus 6A Are Not Required for Virus Replication in Culture and Are Deleted in Virus Stocks That Replicate Well in T-Cell Lines

Human Cytomegalovirus pUL78 G Protein-Coupled Receptor Homologue Is Required for Timely Cell Entry in Epithelial Cells but Not Fibroblasts

The Human Herpesvirus 6 G Protein-Coupled Receptor Homolog U51 Positively Regulates Virus Replication and Enhances Cell-Cell Fusion In Vitro

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