Human Cytomegalovirus UL23 Antagonizes the Antiviral Effect of Interferon-γ by Restraining the Expression of Specific IFN-Stimulated Genes

Interferon-? (IFN-?) is a critical component of innate immune responses in humans to combat infection by many viruses, including human cytomegalovirus (HCMV). IFN-? exerts its biological effects by inducing hundreds of IFN-stimulated genes (ISGs). In this study, RNA-seq analyses revealed that HCMV tegument protein UL23 could regulate the expression of many ISGs under IFN-? treatment or HCMV infection. We further confirmed that among these IFN-? stimulated genes, individual APOL1 (Apolipoprotein-L1), CMPK2 (Cytidine/uridine monophosphate kinase 2), and LGALS9 (Galectin-9) could inhibit HCMV replication. Moreover, these three proteins exhibited a synergistic effect on HCMV replication. UL23-deficient HCMV mutants induced higher expression of APOL1, CMPK2, and LGALS9, and exhibited lower viral titers in IFN-? treated cells compared with parental viruses expressing full functional UL23. Thus, UL23 appears to resist the antiviral effect of IFN-? by downregulating the expression of APOL1, CMPK2, and LGALS9. This study highlights the roles of HCMV UL23 in facilitating viral immune escape from IFN-? responses by specifically downregulating these ISGs.

Automated summary

This study discovered that Interferon-? (IFN-?) plays a crucial role in innate immune responses against human cytomegalovirus (HCMV). It was found that the HCMV tegument protein UL23 could regulate the expression of many IFN-? stimulated genes (ISGs) under IFN-? treatment or HCMV infection. The study also demonstrated that APOL1, CMPK2, and LGALS9, among the ISGs, inhibit HCMV replication and show a synergistic effect. UL23 appears to counteract the antiviral effect of IFN-? by downregulating the expression of APOL1, CMPK2, and LGALS9.