Description:
<jats:title>ABSTRACT</jats:title>
<jats:p>
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
<jats:italic>sry</jats:italic>
or
<jats:italic>tdy</jats:italic>
)-positive donor-derived hematopoietic descendants and Y-chromosome-negative cells of recipients' tissues. The viral genome was found to localize primarily to
<jats:italic>sry</jats:italic>
-negative CD11b
<jats:sup>−</jats:sup>
CD11c
<jats:sup>−</jats:sup>
CD31
<jats:sup>+</jats:sup>
CD146
<jats:sup>+</jats:sup>
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,
<jats:italic>sry</jats:italic>
-positive CD146
<jats:sup>+</jats:sup>
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 10
<jats:sup>4</jats:sup>
LSECs, with an average copy number of 9 (range, 4 to 17) viral genomes. Ex vivo-isolated, latently infected LSECs expressed the viral genes
<jats:italic>m123/ie1</jats:italic>
and
<jats:italic>M122/ie3</jats:italic>
but not
<jats:italic>M11</jats:italic>
<jats:italic>2</jats:italic>
-
<jats:italic>M</jats:italic>
<jats:italic>1</jats:italic>
<jats:italic>13/e1</jats:italic>
,
<jats:italic>M55/gB</jats:italic>
, or
<jats:italic>M86/MCP</jats:italic>
. 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.
</jats:p>