Reactivation of latent Cytomegalovirus (CMV) is an important problem facing clinical transplantation. We have previously described a model for murine CMV (MCMV) reactivation following kidney transplantation using a genetically immunodeficient recipient. We sought to develop a MCMV model that more closely mimics the clinical setting consisting of an immunocompetent recipient treated with a clinically relevant immunosuppression (IS) regimen (anti-lymphocyte serum, FK506 & steroids). We hypothesize that transcriptional reactivation of Immediate Early MCMV genes are induced by ischemia and reperfusion injury early in latently infected kidneys following transplantation, leading lytic replication and dissemination in the presence of IS. To test this, B6 or BALB/c recipients were transplanted with kidneys from BALB/c or B6 mice latently infected, reciprocally, with and without concomitant use of IS. MCMV DNA copy number was determined using qPCR on the 28th and 42nd post-operative day (POD). We observed a significantly increased amplification of viral DNA in both BALB/c and B6 kidney allografts in the IS groups by POD28 compared to day 0 controls. Abundance of viral DNA was significantly higher than the no-IS groups (P<0.01). Viral DNA was detected in other organs in the IS group, suggesting systemic viral dissemination from the kidney graft. Treatment with the same IS regimen failed to induce viral DNA replication in latent infected, non-transplanted B6 or BALB/c mice, supporting that both IS and ischemia reperfusion injury were required for lytic replication and dissemination of MCMV. To identify early putative inflammatory signals that may have triggered transcriptional reactivation, we analyzed plasma from the kidney recipients at POD2 using a protein multi-analyte array. The results revealed a marked up-regulation of IL-18, IL-6, TIMP-1and SAP in the no-IS group compared to controls, while the IS group demonstrated significant downregulation of IL-6 and TIMP-1, but upregulation of IL-18 expression beyond the no-IS group. In summary, transplantation of latently infected kidneys with IS induced MCMV reactivation that correlated with upregulation of inflammatory mediators, providing a clinically relevant MCMV model for further mechanistic investigations.

CITATION INFORMATION: Zhang Z, Yan S, Zhao L, Kurian S, Hummel M, Salomon D, Abecassis M. Clinically Relevant Immunosuppression Promotes MCMV Reactivation and Dissemination Following Transplantation of Latently Infected Kidneys. Am J Transplant. 2017;17 (suppl 3).

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