title: A herpes simplex virus type 1 mutant disrupted for microRNA H2 with increased neurovirulence and rate of reactivation.
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.
authors: 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.
authors: Xianzhi
authors: X
authors: Jiang
authors: Don
authors: D
authors: Brown
authors: Nelson
authors: N
authors: Osorio
authors: Chinhui
authors: C
authors: Hsiang
authors: Lily
authors: L
authors: Li
authors: Lucas
authors: L
authors: Chan
authors: Lbachir
authors: L
authors: BenMohamed
authors: Steven L
authors: SL
authors: Wechsler
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D005260:Female; D015967:Gene Expression Regulation, Viral / Q000235:genetics*; D006561:Herpes Simplex / Q000235:genetics*; D018259:Herpesvirus 1, Human / Q000472:pathogenicity / Q000502:physiology; D017874:Immediate-Early Proteins / Q000096:biosynthesis / Q000235:genetics; D015151:Immunoblotting; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D035683:MicroRNAs / Q000235:genetics*; D012367:RNA, Viral / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D044767:Ubiquitin-Protein Ligases / Q000096:biosynthesis / Q000235:genetics; D014774:Virulence; D014775:Virus Activation / Q000235:genetics*; D017735:Virus Latency / Q000235:genetics
chemical_list: D017874:Immediate-Early Proteins; D035683:MicroRNAs; D012367:RNA, Viral; C477253:latency associated transcript, herpes simplex virus-1; D044767:Ubiquitin-Protein Ligases; C051804:Vmw110 protein, Human herpesvirus 1
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