TNF Receptor Independent Activation of the Cytomegalovirus Major Immediate Early Enhancer in Response to Transplantation

Reactivation of latent human cytomegalovirus (HCMV) infection is a significant risk factor for long term allograft dysfunction. The molecular pathways involved in reactivation of latent virus have not been identified. Previous studies suggested that tumor necrosis factor (TNF) -mediated activation of nuclear factor of kappa light polypeptide gene enhancer in B-cells (NF-kappa B) leading to transcriptional reactivation of viral immediate early (ie) gene expression might be important in transplant-associated viral reactivation. CMV IE gene expression is controlled by the major immediate early promoter/enhancer (MIEP). Because HCMV does not infect mice, transgenic mice carrying a beta-galactosidase reporter gene under the control of the HCMV immediate early enhancer (MIEP-lacZ mice) are a valuable model for studying regulation of CMV IE gene expression in vivo. We have used TNF receptor-deficient MIEP-lacZ (MIEP-lacZ TNFR DKO) mice to study the requirement for TNF in transplant-induced activation of the MIEP.