Human Cytomegalovirus-Encoded Receptor US28 Is Expressed in Renal Allografts and Facilitates Viral Spreading In Vitro

Wouter T. Lollinga*, Raymond H. de Wit, Afsar Rahbar, Gwenda F. Vasse, Belghis Davoudi, Arjan Diepstra, Annelies Riezebos-Brilman, Martin C. Harmsen, Jan-Luuk Hillebrands, Cecilia Soderberg-Naucler, Willem J. van Son, Martine J. Smit, Jan-Stephan Sanders, Jacob van den Born

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

3 Citations (Scopus)

Abstract

BACKGROUND: Renal transplantation is the preferred treatment for patients with end-stage renal disease. Human cytomegalovirus (HCMV) activation is associated with decreased renal graft function and survival. Human cytomegalovirus encodes several immune modulatory proteins, including the G protein-coupled receptor US28, which scavenges human chemokines and modulates intracellular signaling.

METHODS: Our aim was to identify the expression and localization of US28 in renal allograft biopsies by immunohistochemistry and determine its role in viral spreading in vitro.

RESULTS: Immunohistochemistry revealed US28 in 31 of 34 renal transplant biopsies from HCMV-seropositive donors. Expression was independent of HCMV viremia or IgG serostatus. US28 was predominantly expressed in the cytoplasm of vascular smooth muscle cells (VSMCs) and tubular epithelial cells, with a median positivity of 20% and 40%, respectively. Also, US28-positive cells were present within arterial neointima. In contrast to US28, HCMV-encoded immediate early antigen was detected in less than 5% of VSMCs, tubular epithelial cells, interstitial endothelium, interstitial inflammatory infiltrates, and glomerular cells. Primary VSMCs were infected with green fluorescent protein-tagged wild type or US28-deficient HCMV. The viral spreading of US28-deficient HCMV, via culture medium or cell-to-cell transmission, was significantly impeded as shown by green fluorescent protein (ie, infected) cell quantification and quantitative real-time polymerase chain reaction. Additionally, the number and size of foci was smaller.

DISCUSSION: In summary, HCMV-encoded US28 was detected in renal allografts from HCMV-positive donors independent of viremia and serostatus. Also, US28 facilitates HCMV spreading in VSMCs in vitro. Because the vasculature is affected in chronic renal transplant dysfunction, US28 may provide a potential target for therapeutic intervention.

Original languageEnglish
Pages (from-to)531-540
Number of pages10
JournalTransplantation
Volume101
Issue number3
DOIs
Publication statusPublished - Mar-2017

Keywords

  • CHEMOKINE RECEPTOR
  • ENDOTHELIAL-CELLS
  • INFECTION
  • PROTEIN
  • REJECTION
  • PROMOTES
  • GRAFT
  • RECIPIENTS
  • DISEASE
  • IMPACT

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