Immune evasion strategies of roseoloviruses: Characterization of U20, and its potential role as an immunoevasin, and identification of a novel role for HHV-7 U21 in evading NK cell recognition.

摘要

Human herpesviruses 6 (HHV-6) and 7 (HHV-7) comprise the roseolovirus genus of the betaherpesvirus subfamily, and are most closely related to human cytomegalovirus (HCMV). Herpesviruses have evolved numerous immune evasion strategies to facilitate establishment of lifelong persistent infections. While HHV-6 and HHV-7 possess homologs to HCMV genes involved in viral replication, they lack obvious homologs to known HCMV immunoevasins. Instead, roseoloviruses contain clusters of unique open reading frames (ORFs), some of which likely mediate immune evasion. In studies aimed at identifying novel roseolovirus immunoevasins, we characterized one of the unique ORFs, U20. We have demonstrated that U20 is a type I membrane glycoprotein which may be expressed on the surface of infected cells. In contrast to HHV-6B U20, proper trafficking and folding of HHV-7 U20 required viral infection, suggesting a role for other viral proteins in mediating the folding of HHV-7 U20. Using a screen designed to identify cellular proteins whose surface expression was altered upon expression of U20, we identified the Natural Killer (NK) activating ligand ULBP1. NK cells recognize and kill virally infected cells due to increased signaling through NK activating receptors. HHV- 6B U20 binds ULBP1, possibly to prevent ULBP1-mediated signaling through the NK activating receptor NKG2D. Our studies of NKG2D ligands also elucidated a novel role for the HHV-7 immunoevasin U21. Previous studies had demonstrated that HHV-7 U21 binds class I MHC molecules and targets them to lysosomes for degradation to avoid cytotoxic T cell recognition. Here we demonstrate that HHV-7 U21 also interferes with NK cell recognition by downregulating two other NKG2D ligands MICA and MICB. These results suggest that HHV-7 U21 may interfere both with CTL-mediated recognition through the downregulation of class I MHC molecules as well as NK-mediated recognition through downregulation of NK activating ligands.