Expression of the Human Cytomegalovirus UL11 Glycoprotein in Viral Infection and Evaluation of Its Effect on Virus-Specific CD8 T Cells

Gabaev, Ildar; Elbasani, Endrit; Ameres, Stefanie; Steinbrück, Lars; Stanton, Richard J.; Döring, Marius; Roviš, Tihana Lenac; Kalinke, Ulrich; Jonjić, Stipan; Moosmann, Andreas; Messerle, Martin

doi:10.1128/jvi.01691-14

Cited by 22 publications

(32 citation statements)

References 75 publications

(93 reference statements)

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“…Among other specific functions, O-linked glycans may contribute to transport and stable cell surface expression of viral proteins. This has been suggested for HCMV UL11 and for VZV gB (28,110). Interestingly, we identified an ambiguous site FIGURE 3.…”

Section: Discussionsupporting

confidence: 55%

Global Mapping of O-Glycosylation of Varicella Zoster Virus, Human Cytomegalovirus, and Epstein-Barr Virus

Bagdonaite

Nordén

Joshi

et al. 2016

Journal of Biological Chemistry

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Herpesviruses are among the most complex and widespread viruses, infection and propagation of which depend on envelope proteins. These proteins serve as mediators of cell entry as well as modulators of the immune response and are attractive vaccine targets. Although envelope proteins are known to carry glycans, little is known about the distribution, nature, and functions of these modifications. This is particularly true for O-glycans; thus we have recently developed a "bottom up" mass spectrometry-based technique for mapping O-glycosylation sites on herpes simplex virus type 1. We found wide distribution of O-glycans on herpes simplex virus type 1 glycoproteins and demonstrated that elongated O-glycans were essential for the propagation of the virus. Here, we applied our proteome-wide discovery platform for mapping O-glycosites on representative and clinically significant members of the herpesvirus family: varicella zoster virus, human cytomegalovirus, and Epstein-Barr virus. We identified a large number of O-glycosites distributed on most envelope proteins in all viruses and further demonstrated conserved patterns of O-glycans on distinct homologous proteins. Because glycosylation is highly dependent on the host cell, we tested varicella zoster virus-infected cell lysates and clinically isolated virus and found evidence of consistent O-glycosites. These results present a comprehensive view of herpesvirus O-glycosylation and point to the widespread occurrence of O-glycans in regions of envelope proteins important for virus entry, formation, and recognition by the host immune system. This knowledge enables dissection of specific functional roles of individual glycosites and, moreover, provides a framework for design of glycoprotein vaccines with representative glycosylation.

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Section: Discussionsupporting

confidence: 55%

Global Mapping of O-Glycosylation of Varicella Zoster Virus, Human Cytomegalovirus, and Epstein-Barr Virus

Bagdonaite

Nordén

Joshi

et al. 2016

Journal of Biological Chemistry

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“…pUL11 may therefore be more likely to affect CD4 T cell function in vivo . It may also be for this reason that HCMV specific CD8 T cell secretion of IFNγ was not affected by the presence of pUL11 on infected cells [35], in contrast to the results presented here for IL-10 secretion, which is preferentially produced by CD4 T cells [19]. The UL11 protein seems likely to play a role in vivo ; antibodies to pUL11 have been found in patient sera, implying that the protein is expressed at detectable levels [85].…”

Section: Discussionmentioning

confidence: 99%

“…HCMV ΔUL11 is based on the same BAC, but with a deletion of the UL11 ORF and containing the ORF encoding gaussia luciferase in its place (for construction see[35], HCMV HM11DL mutant).…”

Section: Methodsmentioning

confidence: 99%

The human cytomegalovirus glycoprotein pUL11 acts via CD45 to induce T cell IL-10 secretion

et al. 2017

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Human Cytomegalovirus (HCMV) is a widespread pathogen, infection with which can cause severe disease for immunocompromised individuals. The complex changes wrought on the host’s immune system during both productive and latent HCMV infection are well known. Infected cells are masked and manipulated and uninfected immune cells are also affected; peripheral blood mononuclear cell (PBMC) proliferation is reduced and cytokine profiles altered. Levels increase of the anti-inflammatory cytokine IL-10, which may be important for the establishment of HCMV infections and is required for the development of high viral titres by murine cytomegalovirus. The mechanisms by which HCMV affects T cell IL-10 secretion are not understood. We show here that treatment of PBMC with purified pUL11 induces IL-10 producing T cells as a result of pUL11 binding to the CD45 phosphatase on T cells. IL-10 production induced by HCMV infection is also in part mediated by pUL11. Supernatants from pUL11 treated cells have anti-inflammatory effects on untreated PBMC. Considering the mechanism, CD45 can be a positive or negative regulator of TCR signalling, depending on its expression level, and we show that pUL11 also has concentration dependent activating or inhibitory effects on T cell proliferation and on the kinase function of the CD45 substrate Lck. pUL11 is therefore the first example of a viral protein that can target CD45 to induce T cells with anti-inflammatory properties. It is also the first HCMV protein shown to induce T cell IL-10 secretion. Understanding the mechanisms by which pUL11-induced changes in signal strength influence T cell development and function may provide the basis for the development of novel antiviral treatments and therapies against immune pathologies.

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“…T lymphocytes are known to have fundamental roles in controlling HCMV infection, while the virus has also evolved to develop immune evasion mechanisms. For example, it has been demonstrated that the UL11 gene product (pUL11) interferes with the activation and proliferation of T cells 24 , 29 . Because of the sequence similarity between pUL10 and pUL11, exposure of T cells to pUL10 may also hamper proliferation upon cellular activation.…”

Section: Resultsmentioning

confidence: 99%

Human cytomegalovirus pUL10 interacts with leukocytes and impairs TCR‐mediated T‐cell activation

Bruno¹,

Cortese

Monda³

et al. 2016

Immunol Cell Biol

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Human cytomegalovirus (HCMV) is known to exert suppressive effects on the host immune system through expression of various viral genes, thus directly and indirectly affecting antiviral immunity of the infected individuals. We report here that HCMV UL10 encodes a protein (pUL10) with immunosuppressive properties. UL10 has been classified as a member of the HCMV RL11 gene family. Although pUL10 is known to be dispensable for viral replication in cultured cells, its amino-acid sequence is well conserved among different HCMV isolates, suggesting that the protein has a crucial role in viral survival in the host environment. We show that pUL10 is cleaved from the cell surface of fibroblasts as well as epithelial cells and interacts with a cellular receptor ubiquitously expressed on the surface of human leukocytes, demonstrated by ex vivo cell-based assays and flow cytometric analyses on both lymphoid cell lines and primary blood cells. Furthermore, preincubation of peripheral blood mononuclear cells with purified pUL10 ectodomain results in significantly impaired proliferation and substantially reduced pro-inflammatory cytokine production, in particular in CD4 T cells upon in vitro T-cell stimulation. The inhibitory effect of pUL10 is also observed on antigen receptor-mediated intracellular tyrosine phosphorylation in a T-cell line. Based on these observations, we suggest that pUL10 is a newly identified immunomodulatory protein encoded by HCMV. Further elucidation of interactions between pUL10 and the host immune system during HCMV may contribute to finding ways towards new therapies for HCMV infection.

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Expression of the Human Cytomegalovirus UL11 Glycoprotein in Viral Infection and Evaluation of Its Effect on Virus-Specific CD8 T Cells

Cited by 22 publications

References 75 publications

Global Mapping of O-Glycosylation of Varicella Zoster Virus, Human Cytomegalovirus, and Epstein-Barr Virus

Global Mapping of O-Glycosylation of Varicella Zoster Virus, Human Cytomegalovirus, and Epstein-Barr Virus

The human cytomegalovirus glycoprotein pUL11 acts via CD45 to induce T cell IL-10 secretion

Human cytomegalovirus pUL10 interacts with leukocytes and impairs TCR‐mediated T‐cell activation

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