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Publications of the Week

Tripartite Motif 22 (TRIM22) Protein Restricts Herpes Simplex Virus 1 by Epigenetic Silencing of Viral Immediate-Early Genes

By February 9, 2021No Comments

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This week we profile a recent publication in PLOS Pathogens from
Dr. David Knipe and Teja Reddi (pictured) at Blavatnik Institute, Harvard Medical School.

Can you provide a brief overview of your lab’s current research focus?

The Knipe laboratory studies the mechanisms by which herpes simplex virus (HSV) undergoes a productive infection in epithelial cells, versus a latent infection in neurons, where only one transcriptional unit is expressed efficiently. We also investigate the mechanisms of the host immune response to viral infection, and the use of mutant strains of HSV as a herpes vaccine and as a vaccine vector. We are exploring gene editing as an approach to cure herpes simplex virus latency. Please refer to our lab page for more detail on our research interests:

What is the significance of the findings in this publication?

In addition to the well-known arms of the adaptive and the innate immune responses, the host response to viruses includes constitutively expressed genes that suppress or prevent viral infections. Members of the Tripartite Motif (TRIM) superfamily of proteins are key players in this system – including TRIM5 in the human immunodeficiency virus (HIV) inhibition, TRIM19/PML in inhibition of HSV-1. We begin to characterize TRIM22 as a member of the intrinsic immune response against HSV-1 in this publication. TRIM22 inhibits a mutant, replication-defective form of HSV-1, by promoting chromatin compaction of the viral DNA – this in turn reduces viral gene transcripts and downstream viral replication. In fact, we show that TRIM22 can inhibit other DNA viruses to some extent – e.g. human cytomegalovirus (HCMV) and Epstein-Barr virus (EBV). Work done by our collaborators, Dr. So-Yon Lim, and colleagues, show that the TRIM22 gene has differing allelic variants across humans – we begin to explore the host genetic variation in TRIM22 to herpesviral susceptibility. Not only does this work expand knowledge on intrinsic immunity and the anti-viral functions of TRIM22, but it also shows that part of the differential susceptibility of humans to herpesvirus infection is due to genetic variation in TRIM22.

What are the next steps for this research?

We want to define the mechanism by which TRIM22 inhibits the replication of the different herpesviruses (DNA viruses), but also certain RNA viruses. Further, we want to understand how the different human variants affect the activity of TRIM22 in restricting viral replication and determine how we can enhance this restriction activity with the different variant forms and decrease viral infection.

It is also unclear quite how the resourceful HSV-1 escapes TRIM22 mediated inhibition. The viral infected cell polypetide-0 (ICP0) has a number of roles, including degradation of proteins that inhibit viral replication. We, however, found that the TRIM22 protein is not degraded by ICP0. It remains to be determined how the virus evades the intrinsic restriction activity of TRIM22 and whether there are other herpesviral factors that antagonize TRIM22.

TRIM22 is a gene neighbor to TRIM5, one of the first known TRIM genes in having a role in intrinsic immunity. The TRIM5 and TRIM22 gene neighbors evolved under positive selection in hominoids and Old World monkey species, such that they were positively selected in different species. In fact, the rhesus macaque TRIM5α protein inhibits the human immunodeficiency virus-1 (HIV-1) greatly, whereas TRIM22 in humans shows a greater degree of HIV-1 inhibition than human TRIM5. This is a similar pattern to what is observed in the herpesviruses. We previously found that the rhTRIM5α protein was capable of cross-species restriction of human HSV-1, and we report here that the human TRIM22 protein also has an ability to restrict human HSV-1. In contrast, the herpesviral restriction by human TRIM5 is to a much smaller extent. Consequently, we speculate that the dichotomy of the TRIM5 and TRIM22 gene loci is pathogen-driven and due to selection pressures from herpesviruses, in addition to the previously known lentiviruses. This is all the more significant in the context of the pandemic, where cross-species restriction and susceptibility to viruses has become an important arena of investigation.

This work was funded by:

NIH grant AI106934.

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