Journal
JOURNAL OF NEUROVIROLOGY
Volume 21, Issue 2, Pages 199-209Publisher
SPRINGER
DOI: 10.1007/s13365-015-0319-1
Keywords
Herpes simplex virus; Latency associated transcript; MicroRNAH2; Reactivation; Latency; Neurovirulence
Categories
Funding
- Public Health Service NIH grants [R01EY013191, 1R56AI098985, 1R56AI093133, RO1EY019896, RO1EY14900]
- Discovery Center for Eye Research
- NATIONAL CENTER FOR ADVANCING TRANSLATIONAL SCIENCES [UL1TR001414] Funding Source: NIH RePORTER
- NATIONAL EYE INSTITUTE [R01EY019896, R01EY013191, R01EY014900, R01EY024618] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES [R56AI093133, R56AI098985] Funding Source: NIH RePORTER
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The herpes simplex virus type 1 (HSV-1) latency-associated transcript (LAT) encodes several microRNAs. One of these, miR-H2, overlaps and is antisense to the ICP0 gene and appears to decrease expression of the ICP0 protein. To determine if miR-H2 plays a role in the HSV-1 latency-reactivation cycle, we constructed a mutant, McK-Delta H2, in which this microRNA has been disrupted without altering the predicted amino acid sequence of ICP0. McK-Delta H2 produced increased amounts of ICP0. Although replication of McK-Delta H2 was similar to that of its wild-type (wt) McKrae parental virus in RS cells and mouse eyes, McK-Delta H2 was more neurovirulent in Swiss-Webster mice than McKrae based on the percent of mice that died from herpes encephalitis following ocular infection. In addition, using a mouse trigeminal ganglia (TG) explant model of induced reactivation, we show here for the first time that miR-H2 appears to play a role in modulating HSV-1 reactivation. Although the percent of TG from which virus reactivated by day 10 after explant was similar for McK-Delta H2, wt McKrae, and the marker-rescued virus McK-Delta H2Res, at earlier times, significantly more reactivation was seen with McK-Delta H2. Our results suggest that in the context of the virus, miR-H2 downregulates ICP0 and this moderates both HSV-1 neurovirulence and reactivation.
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