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 TRIM5 alpha 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 beta- and gamma- herpesviruses. Allelic variants in TRIM22 showed different degrees of anti-herpesviral activity; thus, TRIM22 genetic variability may contribute to the varying susceptibility to HSV 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.Author summaryThe host immune response to herpesviruses includes intrinsic immunity, which is a constitutively active line of defense. Members of the Tripartite Motif (TRIM) superfamily of proteins, such as cytoplasmic TRIM5 alpha and nuclear TRIM19, are examples of such restriction factors against the prototypical alpha-herpesvirus, herpes simplex virus-1 (HSV-1). Previous reports on the antiviral function of the protein encoded by TRIM22, a gene closely related to the TRIM5 gene, emphasized its antiretroviral role. We show that TRIM22 has an additional role as a restriction factor against herpesviruses. We found that TRIM22 inhibits a mutant form of HSV-1, by promoting chromatin compaction of the viral DNA encoding immediate-early viral genes-this consequently inhibits viral replication and reduces virus yields. Unlike other restriction factors that are degraded by the viral infected cell polypeptide 0 (ICP0), TRIM22 is not degraded by ICP0. We also show that TRIM22 inhibits representative members of the beta-herpesvirus (cytomegalovirus) and gamma- herpesviruses (Epstein-Barr virus). In addition, different TRIM22 genetic variants show differing levels of HSV-1 inhibition. Together, these results argue for the importance of the TRIM22 gene as a restriction factor against herpesviruses, and offer a novel avenue for further investigation on the role of TRIM genes in host genetic variation in herpesviral susceptibility.