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

作者：Jiang Xianzhi; Brown Don; Osorio Nelson; Hsiang Chinhui; Li Lily; Chan Lucas; BenMohamed Lbachir; Wechsler Steven L^*

来源：Journal of NeuroVirology, 2015, 21(2): 199-209.

DOI：10.1007/s13365-015-0319-1

• Herpes simplex virus
• Latency associated transcript
• MicroRNAH2
• Reactivation
• Latency
• Neurovirulence

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.

• 出版日期2015-4