Deletion of the CTRL2 Insulator in HSV-1 Results in the Decreased Expression of Genes Involved in Axonal Transport and Attenuates Reactivation In Vivo

HSV-1 is a human pathogen that establishes a lifelong infection in the host. HSV-1 is transported by retrograde axonal transport to sensory neurons in the peripheral nervous system where latent viral genomes can reactivate. The resulting virus travels via anterograde axonal transport to the peripher...

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Bibliographic Details
Published in:	Viruses Vol. 14; no. 5; p. 909
Main Authors:	Singh, Pankaj, Collins, Matthew F, Johns, Richard N, Manuel, Kayley A, Ye, Ziyun A, Bloom, David C, Neumann, Donna M
Format:	Journal Article
Language:	English
Published:	Switzerland MDPI AG 27-04-2022 MDPI
Subjects:	Animals Anterograde transport Antibiotics Axonal transport Axonal Transport - genetics CCCTC-Binding Factor - genetics CCCTC-Binding Factor - metabolism chromatin CTCF CTCF protein epigenetics Gene expression Gene loci Genome, Viral Genomes Herpes Simplex - genetics Herpes viruses Herpesvirus 1, Human - physiology HSV-1 latency Infections insulator Latency Latent infection Membrane proteins Nervous system Proteins rabbit ocular model Rabbits Sensory neurons United States > US HSV-1 latency rabbit ocular model CTCF chromatin insulator epigenetics
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Summary:	HSV-1 is a human pathogen that establishes a lifelong infection in the host. HSV-1 is transported by retrograde axonal transport to sensory neurons in the peripheral nervous system where latent viral genomes can reactivate. The resulting virus travels via anterograde axonal transport to the periphery and can cause clinical disease. CTCF insulators flank the LAT and IE regions of HSV-1 and during latency and maintain the integrity of transcriptional domains through a myriad of functions, including enhancer-blocking or barrier-insulator functions. Importantly, during reactivation, CTCF protein is evicted from the HSV-1 genome, especially from the CTRL2 insulator. CTRL2 is a functional insulator downstream of the 5'exon region of the LAT, so these results suggest that the disruption of this insulator may be required for efficient HSV-1 reactivation. To further explore this, we used a recombinant virus containing a deletion of the CTRL2 insulator (ΔCTRL2) in a rabbit ocular model of HSV-1 infection and induced reactivation. We show that, in the absence of the CTRL2 insulator, HSV-1 established an equivalent latent infection in rabbits, but those rabbits failed to efficiently reactivate from latency. Furthermore, we found a significant decrease in the expression of the gene Us9-, a gene that codes for a type II membrane protein that has been shown to be required for anterograde transport in neurons. Taken together, these results suggest that the functions of the CTRL2 insulator and Us9 activation in reactivating neurons are intrinsically linked through the regulation of a gene responsible for the axonal transport of HSV-1 to the periphery.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	1999-4915 1999-4915
DOI:	10.3390/v14050909