Inter‐ and Intragenic Variations Complicate the Molecular Epidemiology of Human Cytomegalovirus

Rasmussen, Lucy; Geissler, Aimee; Winters, Mark A.

doi:10.1086/367900

Cited by 92 publications

(92 citation statements)

References 73 publications

(54 reference statements)

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“…This conclusion is consistent with the model of gH/gL/gO providing a core entry function since all gO isoforms must leave critical surfaces on gH/gL available for interaction with gB. These results are also consistent with those of Rasmussen et al, who investigated genetic linkages of polymorphic loci in clinical HCMV isolates and found evidence of several combinations of gH/gL and gO isoforms (61).…”

Section: Discussionsupporting

confidence: 91%

Comparative Analysis of gO Isoforms Reveals that Strains of Human Cytomegalovirus Differ in the Ratio of gH/gL/gO and gH/gL/UL128-131 in the Virion Envelope

Zhou

Wechsler

et al. 2013

J Virol

142

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Herpesvirus glycoprotein complex gH/gL provides a core entry function through interactions with the fusion protein gB and can also influence tropism through receptor interactions. The Epstein-Barr virus gH/gL and gH/gL/gp42 serve both functions for entry into epithelial and B cells, respectively. Human cytomegalovirus (HCMV) gH/gL can be bound by the UL128-131 proteins or gO. The phenotypes of gO and UL128-131 mutants suggest that gO-gH/gL interactions are necessary for the core entry function on all cell types, whereas the binding of UL128-131 to gH/gL likely relates to a distinct receptor-binding function for entry into some specific cell types (e.g., epithelial) but not others (e.g., fibroblasts and neurons). There are at least eight isoforms of gO that differ by 10 to 30% of amino acids, and previous analysis of two HCMV strains suggested that some isoforms of gO function like chaperones, disassociating during assembly to leave unbound gH/gL in the virion envelope, while others remain bound to gH/gL. For the current report, we analyzed the gH/gL complexes present in the virion envelope of several HCMV strains, each of which encodes a distinct gO isoform. Results indicate that all strains of HCMV contain stable gH/gL/gO trimers and gH/gL/UL128-131 pentamers and little, if any, unbound gH/gL. TR, TB40/e, AD169, and PH virions contained vastly more gH/gL/gO than gH/gL/UL128-131, whereas Merlin virions contained mostly gH/gL/UL128-131, despite abundant unbound gO remaining in the infected cells. Suppression of UL128-131 expression during Merlin replication dramatically shifted the ratio toward gH/gL/gO. These data suggest that Merlin gO is less efficient than other gO isoforms at competing with UL128-131 for binding to gH/gL. Thus, gO diversity may influence the pathogenesis of HCMV through effects on the assembly of the core versus tropism gH/gL complexes.

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Section: Discussionsupporting

confidence: 91%

Comparative Analysis of gO Isoforms Reveals that Strains of Human Cytomegalovirus Differ in the Ratio of gH/gL/gO and gH/gL/UL128-131 in the Virion Envelope

Zhou

Wechsler

et al. 2013

J Virol

142

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“…Although there are some clusters of variable ORFs, e.g., UL58-UL68, variable ORFs are spread across the genome. Variability among clinical isolates has been reported for several HCMV ORFs, such as the UL55-coded glycoprotein B (32)(33)(34)(35), for which different sequence types have been associated with increased risk of disease in bone marrow transplant patients (36).…”

Section: Resultsmentioning

confidence: 99%

Coding potential of laboratory and clinical strains of human cytomegalovirus

Murphy

Yü

Grimwood

et al. 2003

Proc. Natl. Acad. Sci. U.S.A.

465

451

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Six strains of human cytomegalovirus have been sequenced, including two laboratory strains (AD169 and Towne) that have been extensively passaged in fibroblasts and four clinical isolates that have been passaged to a limited extent in the laboratory (Toledo, FIX, PH, and TR). All of the sequenced viral genomes have been cloned as infectious bacterial artificial chromosomes. A total of 252 ORFs with the potential to encode proteins have been identified that are conserved in all four clinical isolates of the virus. Multiple sequence alignments revealed substantial variation in the amino acid sequences encoded by many of the conserved ORFs

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“…Also among this group are genes UL146 (27,35,36,(66)(67)(68) and UL74 (gO) (27,35,(69)(70)(71), which are well characterized because of their utility in genotyping clinical isolates. The selection pressures responsible for generating such degrees of divergence are not fully understood, but their origins, and perhaps the era in which they have operated, appears to be ancient (66).…”

Section: Discussionmentioning

confidence: 99%

Reconstruction of the complete human cytomegalovirus genome in a BAC reveals RL13 to be a potent inhibitor of replication

Stanton¹,

Baluchova²,

Dargan³

et al. 2010

J. Clin. Invest.

240

375

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Human cytomegalovirus (HCMV) in clinical material cannot replicate efficiently in vitro until it has adapted by mutation. Consequently, wild-type HCMV differ fundamentally from the passaged strains used for research. To generate a genetically intact source of HCMV, we cloned strain Merlin into a self-excising BAC. The Merlin BAC clone had mutations in the RL13 gene and UL128 locus that were acquired during limited replication in vitro prior to cloning. The complete wild-type HCMV gene complement was reconstructed by reference to the original clinical sample. Characterization of viruses generated from repaired BACs revealed that RL13 efficiently repressed HCMV replication in multiple cell types; moreover, RL13 mutants rapidly and reproducibly emerged in transfectants. Virus also acquired mutations in genes UL128, UL130, or UL131A, which inhibited virus growth specifically in fibroblast cells in wild-type form. We further report that RL13 encodes a highly glycosylated virion envelope protein and thus has the potential to modulate tropism. To overcome rapid emergence of mutations in genetically intact HCMV, we developed a system in which RL13 and UL131A were conditionally repressed during virus propagation. This technological advance now permits studies to be undertaken with a clonal, characterized HCMV strain containing the complete wild-type gene complement and promises to enhance the clinical relevance of fundamental research on HCMV.

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Inter‐ and Intragenic Variations Complicate the Molecular Epidemiology of Human Cytomegalovirus

Cited by 92 publications

References 73 publications

Comparative Analysis of gO Isoforms Reveals that Strains of Human Cytomegalovirus Differ in the Ratio of gH/gL/gO and gH/gL/UL128-131 in the Virion Envelope

Comparative Analysis of gO Isoforms Reveals that Strains of Human Cytomegalovirus Differ in the Ratio of gH/gL/gO and gH/gL/UL128-131 in the Virion Envelope

Coding potential of laboratory and clinical strains of human cytomegalovirus

Reconstruction of the complete human cytomegalovirus genome in a BAC reveals RL13 to be a potent inhibitor of replication

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