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A herpes simplex virus type 1 mutant disrupted for microRNA H2 with increased neurovirulence and rate of reactivation

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Abstract

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-ΔH2, in which this microRNA has been disrupted without altering the predicted amino acid sequence of ICP0. McK-ΔH2 produced increased amounts of ICP0. Although replication of McK-ΔH2 was similar to that of its wild-type (wt) McKrae parental virus in RS cells and mouse eyes, McK-ΔH2 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-ΔH2, wt McKrae, and the marker-rescued virus McK-ΔH2Res, at earlier times, significantly more reactivation was seen with McK-ΔH2. 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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Acknowledgments

This study was supported by Public Health Service NIH grants R01EY013191, 1R56AI098985, 1R56AI093133, RO1EY019896, and RO1EY14900, and The Discovery Center for Eye Research. We thank Dr. Nigel Fraser for reading this manuscript and providing helpful comments.

Conflict of interest

All of the authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. Virology Research, Gavin Herbert Eye Institute and Department of Ophthalmology, School of Medicine, University of California, Irvine, 843 Health Sciences Road, Hewitt Hall (Building 843), Room 2012, Irvine, CA, 92697, USA

    Xianzhi Jiang, Don Brown, Nelson Osorio, Chinhui Hsiang, Lily Li, Lucas Chan, Lbachir BenMohamed & Steven L. Wechsler

  2. Laboratory of Cellular and Molecular Immunology, Gavin Herbert Eye Institute and Department of Ophthalmology, School of Medicine, University of California, Irvine, Irvine, CA, 92697, USA

    Lbachir BenMohamed

  3. Chao Family Comprehensive Cancer Center, University of California, Irvine Medical Center, Irvine, CA, 92868-32013, USA

    Lbachir BenMohamed

  4. Institute for Immunology, School of Medicine, University of California, Irvine, Irvine, CA, 92697, USA

    Lbachir BenMohamed

  5. Department of Microbiology and Molecular Genetics, School of Medicine, University of California, Irvine, Irvine, CA, 92697, USA

    Steven L. Wechsler

  6. Center for Virus Research, University of California, Irvine, Irvine, CA, 92697, USA

    Steven L. Wechsler

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  1. Xianzhi Jiang
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Correspondence to Steven L. Wechsler.

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Jiang, X., Brown, D., Osorio, N. et al. A herpes simplex virus type 1 mutant disrupted for microRNA H2 with increased neurovirulence and rate of reactivation. J. Neurovirol. 21, 199–209 (2015). https://doi.org/10.1007/s13365-015-0319-1

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  • DOI: https://doi.org/10.1007/s13365-015-0319-1

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