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Journal of Virology, September 2009, p. 8869-8884, Vol. 83, No. 17
0022-538X/09/$08.00+0     doi:10.1128/JVI.00870-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Liver Sinusoidal Endothelial Cells Are a Site of Murine Cytomegalovirus Latency and Reactivation{triangledown}

Christof K. Seckert, Angélique Renzaho, Hanna-Mari Tervo, Claudia Krause, Petra Deegen, Birgit Kühnapfel, Matthias J. Reddehase,* and Natascha K. A. Grzimek

Institute for Virology, University Medical Center of the Johannes Gutenberg University, Mainz, Germany

Received 30 April 2009/ Accepted 11 June 2009

Latent cytomegalovirus (CMV) is frequently transmitted by organ transplantation, and its reactivation under conditions of immunosuppressive prophylaxis against graft rejection by host-versus-graft disease bears a risk of graft failure due to viral pathogenesis. CMV is the most common cause of infection following liver transplantation. Although hematopoietic cells of the myeloid lineage are a recognized source of latent CMV, the cellular sites of latency in the liver are not comprehensively typed. Here we have used the BALB/c mouse model of murine CMV infection to identify latently infected hepatic cell types. We performed sex-mismatched bone marrow transplantation with male donors and female recipients to generate latently infected sex chromosome chimeras, allowing us to distinguish between Y-chromosome (gene sry or tdy)-positive donor-derived hematopoietic descendants and Y-chromosome-negative cells of recipients' tissues. The viral genome was found to localize primarily to sry-negative CD11b– CD11c– CD31+ CD146+ cells lacking major histocompatibility complex class II antigen (MHC-II) but expressing murine L-SIGN. This cell surface phenotype is typical of liver sinusoidal endothelial cells (LSECs). Notably, sry-positive CD146+ cells were distinguished by the expression of MHC-II and did not harbor latent viral DNA. In this model, the frequency of latently infected cells was found to be 1 to 2 per 104 LSECs, with an average copy number of 9 (range, 4 to 17) viral genomes. Ex vivo-isolated, latently infected LSECs expressed the viral genes m123/ie1 and M122/ie3 but not M112-M113/e1, M55/gB, or M86/MCP. Importantly, in an LSEC transfer model, infectious virus reactivated from recipients' tissue explants with an incidence of one reactivation per 1,000 viral-genome-carrying LSECs. These findings identified LSECs as the main cellular site of murine CMV latency and reactivation in the liver.

* Corresponding author. Mailing address: University Medical Center of the Institute for Virology, Johannes Gutenberg University, Hochhaus am Augustusplatz, 55131 Mainz, Germany. Phone: 49-6131-39-33650. Fax: 49-6131-39-35604. E-mail: Matthias.Reddehase{at}uni-mainz.de

{triangledown} Published ahead of print on 17 June 2009.

Journal of Virology, September 2009, p. 8869-8884, Vol. 83, No. 17
0022-538X/09/$08.00+0     doi:10.1128/JVI.00870-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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