Human cytomegalovirus (HCMV) is a ubiquitous pathogen infecting 60- 100% of the world population. In populations that are immunosuppressed including AIDS patients, transplant recipients, and neonates who have immature immune systems this virus causes severe disease and morbidity. After primary infection of the host via contact with contaminated body fluids the virus persists in the host and establishes latency. The virus reactivates from latency multiple times and is shed in the host body fluids. The ability of HCMV to establish such lifelong infections is attributed in part to its ability to modulate various aspects of host immune responses.
Central to the antiviral immune response of the host is interferon (IFN) mediated activation of cellular gene products that interfere with various aspects of the viral life cycle. It is known that IFN mediated signaling is attenuated in HCMV infected cells. We set out to identify the HCMV gene products that are involved in modulating IFN signaling and elucidate their mode of action. For this purpose we constructed a cDNA library of HCMV laboratory strain AD169. Characterization of this cDNA library revealed an abundance of non protein coding transcripts and transcripts in antisense orientation to known or predicted HCMV genes. We screened this cDNA library for genes that disrupt IFN signaling, and the UL123 gene encoding the IE1 protein was the first candidate gene identified. Our results indicate that IE1 can attenuate both type I and type II IFN signaling. We found that IE1 does not inhibit the proximal events of type II IFN signaling but it interferes with STAT1 binding to target DNA elements. Using a series of truncation mutants we were able to map this function to the C terminal domain of the IE1 protein. Our data indicate that a novel mechanism is employed by IE1 to interfere with the association of STAT1 with its target DNA.
The research findings presented here reveal the increased complexity of the HCMV transcriptome and a potentially novel mechanism of viral attenuation of IFN signaling. This enhanced understanding of HCMV biology may have implications in the development of antiviral drugs and vaccines.