Cytomegalovirus (CMV) is a ubiquitous pathogen that causes a persistent, lifelong infection in immunocompetent hosts. CMV disease is a common cause of morbidity and mortality in immunocompromised individuals, particularly transplant recipients and AIDS patients. Chronic infection occurs despite the fact that significant anti-CMV adaptive (e.g. cytotoxic, humoral) and innate (e.g. interferon (IFN), NK cells) immune responses are continually present. While host immunity is effective at controlling CMV infection, it is unable to fully eradicate the virus' most likely due to a range of viral immune evasion mechanisms. IFN-stimulated genes (ISGs) represent an early host innate response meant to intracellularly inhibit virus replication. Counteraction by interference with ISG expression has been shown for many viruses yet paradoxically, strong ISG induction is observed in fibroblasts infected with human CMV (HCMV) laboratory strain AD169. Using DNA microarrays we previously demonstrated that the viral glycoprotein B (gB) is the major determinant for this induction, which takes place through activation of IFN regulatory factor 3 (IRF3). In contrast to AD169 however, our microarray studies using CMV from Rhesus macaque (RhCMV) reveal an absence of both ISG induction and IRF3 activation in infected cells. In the absence of RhCMV gene expression, however, ISGs were strongly induced. We thus hypothesize that RhCMV encodes gene(s) whose product(s) interfere with the induction of ISGs by gB and the nuclear translocation of IRF3. We also observed that clinical strains of HCMV induced ISGs much less than AD169, suggesting interference with ISG expression may be critical for survival in the host. Thus, in contrast to the current theory that CMV is unable to interfere with IRF3 activation and that ISG induction might even be beneficial for the virus, our data suggest that prevention of ISG induction might be essential for CMV pathogenesis. The major goals of this proposal include identification of 1) RhCMV gene(s) required for ISG downregulation and 2) host pathways targeted by the virus to accomplish this. ? ? ?
| DeFilippis, Victor R; Robinson, Bridget; Keck, Thomas M et al. (2006) Interferon regulatory factor 3 is necessary for induction of antiviral genes during human cytomegalovirus infection. J Virol 80:1032-7 |
