Tripartite Motif 22 (TRIM22) protein restricts herpes simplex virus 1 by epigenetic silencing of viral immediate-early genes.

Intrinsic resistance is a crucial line of defense against virus infections, and members of the Tripartite Ring Interaction Motif (TRIM) family of proteins are major players in this system, such as cytoplasmic TRIM5α or nuclear promyelocytic leukemia (PML/TRIM19) protein. Previous reports on the antiviral function of another TRIM protein, TRIM22, emphasized its innate immune role as a Type I and Type II interferon-stimulated gene against RNA viruses. This study shows that TRIM22 has an additional intrinsic role against DNA viruses. Here, we report that TRIM22 is a novel restriction factor of HSV-1 and limits ICP0-null virus replication by increasing histone occupancy and heterochromatin, thereby reducing immediate-early viral gene expression. The corresponding wild-type equivalent of the virus evades the TRIM22-specific restriction by a mechanism independent of ICP0-mediated degradation. We also demonstrate that TRIM22 inhibits other DNA viruses, including representative members of the β- and γ- herpesviruses. Allelic variants in TRIM22 showed different degrees of anti-herpesviral activity; thus, TRIM22 genetic variability may contribute to the varying susceptibility to HSV-1 infection in humans. Collectively, these results argue that TRIM22 is a novel restriction factor and expand the list of restriction factors functioning in the infected cell nucleus to counter DNA virus infection.