Interferons (IFNs) are
cytokines that induce a global change in the cell to establish
antiviral immunity. We previously demonstrated that human adenovirus (HAdV) exploits IFN-induced viral repression to persist in infected cells. Although this in vitro persistence model has been described, the mechanism behind how persistent HAdV
infection is established is not well understood. In this study, we demonstrate that IFN signaling is essential for viral repression and promoting
persistent infection.
Cyclin-dependent kinase 4 (CDK4), an antagonist of
retinoblastoma (Rb) family
proteins, was shown to disrupt the viral repression induced by IFNs. Consistent with this result, knockout of the Rb family
proteins pRb, p107, and/or p130 drastically reduced the effect of IFNs on viral replication. The pRb
protein specifically contributed the greatest effect to IFN inhibition of viral replication. Interestingly, IFNs did not impact pRb through direct changes in
protein or phosphorylation levels. Cells treated with IFNs continued to cycle normally, consistent with observations that persistently infected cells remain for long periods of time in the host and in our in vitro
persistent infection model. Finally, we observed that
histone deacetylase (
HDAC) inhibitors activated productive viral replication in persistently infected cells in the presence of IFN. Thus, HDACs, specifically class I HDACs, which are commonly associated with Rb family
proteins, play a major role in the maintenance of persistent HAdV
infection in vitro. This study uncovers the critical role of pRb and class I HDACs in the IFN-induced formation of a repressor complex that promotes persistent HAdV
infections. IMPORTANCE Adenoviruses are ubiquitous viruses infecting more than 90% of the human population. HAdVs cause
persistent infections that may lead to serious complications in immunocompromised patients. Therefore, exploring how HAdVs establish
persistent infections is critical for understanding viral reactivation in immunosuppressed individuals. The mechanism underlying HAdV persistence has not been fully explored. Here, we provide insight into the contributions of the host cell to IFN-mediated persistent HAdV
infection. We found that HAdV-C5 productive
infection is inhibited by an Rb-E2F-HDAC repressor complex. Treatment with
HDAC inhibitors converted a
persistent infection to a lytic
infection. Our results suggest that this process involves the noncanonical regulation of Rb-E2F signaling. This study provides insight into a highly prevalent human pathogen, bringing a new level of complexity and understanding to the replicative cycle.