Human cytomegalovirus glycoprotein complex gH/gL/gO uses PDGFR-α as a key for entry

Wu, Youmei; Prager, Adrian; Simone, Boos; Moritz, Resch; Brizić, Ilija; Mach, Michael; Wildner, Sabrina; Scrivano, Laura; Adler, Barbara

doi:10.1371/journal.ppat.1006281

Cited by 143 publications

(186 citation statements)

References 58 publications

(130 reference statements)

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“…These data are well in line with previous reports showing the inhibitory capacity of sPDGFRα for several distinct HCMV strains (26). Notably, even at a concentration of 1.25μg/ml sPDGFRα we observed a residual infectivity of about 1 - 2% in epithelial cells, while in fibroblasts the inhibition was almost complete (≥ 99%) similar as shown previously (27). Thus, it is tempting to speculate that a trimer-independent entry mechanism accounts for the residual infectivity.…”

Section: Discussionsupporting

confidence: 90%

“…Over the last few years, a number of cellular interaction partners for both, the trimer and the pentamer have been identified (14). One of these cellular receptors, platelet-derived growth factor receptor alpha (PDGFRα), was identified to directly and specifically interact with gO parts of the trimer (25–27). This interaction enables entry of cell-free virions into fibroblasts, the only cell type which shows a high PDGFRα expression (28).…”

Section: Introductionmentioning

confidence: 99%

“…This interaction enables entry of cell-free virions into fibroblasts, the only cell type which shows a high PDGFRα expression (28). Albeit, soluble forms of PDGFRα (sPDGFRα) can severely inhibit not only entry into fibroblasts, but also entry into endothelial and epithelial cells (25–27), and first observations indicate that the inhibitory capacity of sPDGFRα is effective against several HCMV strains even when they harbour a different gO genotype sequence (26).…”

Section: Introductionmentioning

confidence: 99%

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Influence of human cytomegalovirus glycoprotein O polymorphism on the inhibitory effect of soluble forms of trimer- and pentamer-specific entry receptors

Brait

Stögerer

Kalser

et al. 2019

Preprint

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AbstractHuman cytomegalovirus (HCMV) envelope glycoprotein complexes, gH/gL/gO-trimer and gH/gL/UL128L-pentamer, are important for cell-free HCMV entry. While soluble Nrp2-Fc (sNrp2-Fc) interferes with epithelial/endothelial cell entry through UL128, soluble PDGFRα-Fc (sPDGFRα-Fc) interacts with gO thereby inhibiting infection of all cell types. Since gO is the most variable subunit we investigated the influence of gO polymorphism on the inhibitory capacities of sPDGFRα-Fc and sNRP2-Fc.Accordingly, gO genotype 1c (GT1c) sequence was fully or partially replaced by gO GT2b, GT3, GT5 sequences in TB40-BAC4-luc background. All mutants were tested for fibroblast and epithelial cell infectivity, for virions’ gO and gH content, and for infection inhibition by sPDGFRα-Fc and sNrp2-Fc.Full-length and partial gO GT swapping may strongly alter the virions’ gO and gH levels associated with enhanced epithelial cell infectivity. All gO GT mutants except recombinant gO GT1c/3 displayed a near-complete inhibition at 1.25 μg/ml sPDGFRα-Fc on epithelial cells (98% versus 91%) and all on fibroblasts (≥ 99%). While gO GT replacement did not influence sNrp2-Fc inhibition at 1.25 μg/ml on epithelial cells (96%-98%), it rendered mutants with low gO levels moderately accessible to fibroblasts inhibition (20%-40%). In contrast to the steep sPDGFRα-Fc inhibition curves (slope >1.0), sNrp2-Fc dose-response curves on epithelial cells displayed slopes of ~1.0 suggesting functional differences between these entry inhibitors.Our findings suggest that targeting of gO-trimer rather than UL128-pentamer might be a promising target to inhibit infectivity independent of the cell type, gO polymorphism, and gO/gH content. However, intragenic gO recombination may lead to moderate resistence to sPDGFRα-Fc inhibition.ImportanceHuman cytomegalovirus (HCMV) is known for its broad cell tropism as reflected by the different organs and tissues affected by HCMV infection. Hence, inhibition of HCMV entry into distinct cell types could be considered as a promising therapeutic option to limit cell-free HCMV infection. Soluble forms of cellular entry receptor PDGFRα rather than those of entry receptor neuropilin-2 inhibit infection of multiple cell types. sPDGFRα specifically interacts with gO of the trimeric gH/gL/gO envelope glycoprotein complex. HCMV strains may differ with respect to the virions’ amount of trimer and the highly polymorphic gO sequence. In this study, we show that gO polymorphism rather than gO levels may affect the inhibitory capacity of sPDGFRα. The finding that gO intragenic recombination may lead to moderate evasion from sPDGFRα inhibition is of major value to the development of potential anti-HCMV therapeutic compounds based on sPDGFRα.

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Section: Discussionsupporting

confidence: 90%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Influence of human cytomegalovirus glycoprotein O polymorphism on the inhibitory effect of soluble forms of trimer- and pentamer-specific entry receptors

Brait

Stögerer

Kalser

et al. 2019

Preprint

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“…In more detail, gH/gL may be complexed either with pUL128L, giving rise to the PC gH/gL/ pUL128L, or UL74-encoded gO, thus forming the trimeric complex gH/gL/gO, which binds to platelet-derived growth factor receptor a and mediates HCMV entry into HELFs [57][58][59]. Thus, gH/gL/gO and PC were considered to represent two mutually exclusive cell entry complexes, as suggested by mass spectrometry and mutagenesis analysis [60].…”

Section: Genetic Determinants Of Endothelial Cells and Leukocyte Tropismmentioning

confidence: 99%

The pentameric complex of human Cytomegalovirus: cell tropism, virus dissemination, immune response and vaccine development

Gerna

Revello

Baldanti

et al. 2017

Journal of General Virology

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Between the 1980s and 1990s, three assays were developed for diagnosis of human cytomegalovirus (HCMV) infections: leuko (L)-antigenemia, L-viremia and L-DNAemia, detecting viral protein pp65, infectious virus and viral DNA, respectively, in circulating leukocytes Repeated initial attempts to reproduce the three assays in vitro using laboratory-adapted strains and infected cell cultures were consistently unsuccessful. Results were totally reversed when wild-type HCMV strains were used to infect either fibroblasts or endothelial cells. Careful analysis and sequencing of plaque-purified viruses from recent clinical isolates drew attention to the ULb¢ region of the HCMV genome. Using bacterial artificial chromosome technology, it was shown by both gain-of-function and loss-of-function experiments that UL131-128 genes are indispensable for virus growth in endothelial cells and virus transfer to leukocytes. In addition, a number of clinical isolates passaged in human fibroblasts had lost both properties (leuko-tropism and endothelial cell-tropism) when displaying a mutation in the UL131-128 locus

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“…demonstrated that HCMV gB directly interacts with PDGFR-α resulting in receptor tyrosine phosphorylation, indicating that PDGFR-α is a more critical receptor required for HCMV entry than EGFR. Wu et al46 reported that the HCMV glycoprotein complex gH/gL/gO binds to PDGFR-α on the surface of fibroblasts and that gH/gL/gO either directly or indirectly recruits gB to this complex. Additionally, PDGFR-α functions as an entry receptor for HCMV expressing gH/gL/gO, but not for HCMV mutants lacking the gH/gL/gO complex.The EGFR and PDGFR have been shown to perform a similar function and trigger the PI3K/Akt pathway upon virus entry.…”

mentioning

confidence: 99%

Mechanisms of human cytomegalovirus infection with a focus on epidermal growth factor receptor interactions

Falcão

Vasconcelos

Silva

et al. 2017

Reviews in Medical Virology

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Human cytomegalovirus (HCMV) is a widespread opportunistic herpesvirus that causes severe diseases in immunocompromised individuals. It has a high prevalence worldwide that is linked with socioeconomic factors. Similar to other herpesviruses, HCMV has the ability to establish lifelong persistence and latent infection following primary exposure. HCMV infects a broad range of cell types. This broad tropism suggests that it may use multiple receptors for host cell entry. The identification of receptors used by HCMV is essential for understanding viral pathogenesis, because these receptors mediate the early events necessary for infection. Many cell surface components have been identified as virus receptors, such as epidermal growth factor receptor (EGFR), which is characterized by tyrosine kinase activity and plays a crucial role in the control of key cellular transduction pathways. EGFR is essential for HCMV binding, signaling, and host cell entry. This review focuses on HCMV infection via EGFR on different cell types and its implications for the cellular environment, viral persistence, and infection.

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Human cytomegalovirus glycoprotein complex gH/gL/gO uses PDGFR-α as a key for entry

Cited by 143 publications

References 58 publications

Influence of human cytomegalovirus glycoprotein O polymorphism on the inhibitory effect of soluble forms of trimer- and pentamer-specific entry receptors

Influence of human cytomegalovirus glycoprotein O polymorphism on the inhibitory effect of soluble forms of trimer- and pentamer-specific entry receptors

The pentameric complex of human Cytomegalovirus: cell tropism, virus dissemination, immune response and vaccine development

Mechanisms of human cytomegalovirus infection with a focus on epidermal growth factor receptor interactions

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