Numerous Conserved and Divergent MicroRNAs Expressed by Herpes Simplex Viruses 1 and 2

Jurak, Igor; Kramer, Martha F.; Mellor, Joseph; Lint, Alison L. van; Roth, Frederick P.; Knipe, David M.; Coen, Donald M.

doi:10.1128/jvi.02725-09

Cited by 145 publications

(210 citation statements)

References 68 publications

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“…2A). Sequences deriving from in or around the OriLyt of both rat and mouse cytomegaloviruses (RCMV and MCMV, respectively), as well as some other herpesviruses, such as herpes simplex virus 1 (HSV-1) and HSV-2, have previously been reported to encode miRNAs or postulated to act as RNA primers for the replication of the viral genome (8,17,30,35).…”

Section: Resultsmentioning

confidence: 99%

Small RNA Deep Sequencing Identifies MicroRNAs and Other Small Noncoding RNAs from Human Herpesvirus 6B

Tuddenham

Jung

Chane-Woon-Ming

et al. 2012

J Virol

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Roseolovirus, or human herpesvirus 6 (HHV-6), is a ubiquitous human pathogen infecting over 95% of the population by the age of 2 years. As with other herpesviruses, reactivation of HHV-6 can present with severe complications in immunocompromised individuals. Recent studies have highlighted the importance of herpesvirus-derived microRNAs (miRNAs) in modulating both cellular and viral gene expression. An initial report which computed the likelihood of various viruses to encode miRNAs did not predict HHV-6 miRNAs. To experimentally screen for small HHV-6-encoded RNAs, we conducted large-scale sequencing of Sup-T-1 cells lytically infected with a laboratory strain of HHV-6B. This revealed an abundant, 60-to 65-nucleotide RNA of unknown function derived from the lytic origin of replication (OriLyt) that gave rise to smaller RNA species of 18 or 19 nucleotides. In addition, we identified four pre-miRNAs whose mature forms accumulated in Argonaute 2. In contrast to the case for other betaherpesviruses, HHV-6B miRNAs are expressed from direct repeat regions (DR L and DR R ) located at either side of the genome. All miRNAs are conserved in the closely related HHV-6A variant, and one of them is a seed ortholog of the human miRNA miR-582-5p. Similar to alphaherpesvirus miRNAs, they are expressed in antisense orientation relative to immediateearly open reading frames (ORFs) and thus have the potential to regulate key viral genes.

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Section: Resultsmentioning

confidence: 99%

Small RNA Deep Sequencing Identifies MicroRNAs and Other Small Noncoding RNAs from Human Herpesvirus 6B

Tuddenham

Jung

Chane-Woon-Ming

et al. 2012

J Virol

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“…HSV-1 encodes 16 miRNA identified by deep-sequencing studies of virus-infected cells; 11 of these miRNAs are encoded within or near to the LAT gene (Jurak et al, 2010) with seven detected in latently infected mouse or human ganglia (Umbach et al, 2009;Held et al, 2011; Kramer et al, 2011). Three HSV-1 miRNAs are antisense to, and reduce expression of, virus genes involved in the initiation of virus gene transcription (ICP4), neurovirulence (ICP34.5) and inactivation of host antiviral pathways (ICP0/RL2) (Umbach et al, 2008; Flores et al, 2013).…”

Section: During Latency Hsv-1 and Vzv Gene Transcription Is Restrictedmentioning

confidence: 99%

“…Specifically, promoters for HSV-1 genes expressed during lytic infection (ICP4, ICP27 and ICP8) are associated with H3K9 and H3K27 trimethylations in ganglia of latently infected mice, and these post-translational modifications indicative of facultative heterochromatin are reduced when latency is established with HSV-1 containing mutations precluding LAT transcription (Amelio et al, 2006a;Cliffe et al, 2009; Kwiatkowski et al, 2009). Interestingly, LAT-dependent heterochromatin formation (H3K27me 3 ) on lytic virus promoters during establishment of latency -a phenomenon that is virus strain and infection model-specific -may involve modifications of host polycomb repressor complex group 2 protein (PRC-2) as Suz12, a normal PRC-2 component, is not detected on latent HSV-1 DNA during silencing of the virus genome (Kwiatkowski et al, 2009;Cliffe et al, 2013).HSV-1 encodes 16 miRNA identified by deep-sequencing studies of virus-infected cells; 11 of these miRNAs are encoded within or near to the LAT gene (Jurak et al, 2010) with seven detected in latently infected mouse or human ganglia (Umbach et al, 2009;Held et al, 2011; Kramer et al, 2011). Three HSV-1 miRNAs are antisense to, and reduce expression of, virus genes involved in the initiation of virus gene transcription (ICP4), neurovirulence (ICP34.5) and inactivation of host antiviral pathways (ICP0/RL2) (Umbach et al, 2008; Flores et al, 2013).…”

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confidence: 99%

A comparison of herpes simplex virus type 1 and varicella-zoster virus latency and reactivation

Kennedy

Rovnak

Badani

et al. 2015

Journal of General Virology

133

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Herpes simplex virus type 1 (HSV-1; human herpesvirus 1) and varicella-zoster virus (VZV; human herpesvirus 3) are human neurotropic alphaherpesviruses that cause lifelong infections in ganglia. Following primary infection and establishment of latency, HSV-1 reactivation typically results in herpes labialis (cold sores), but can occur frequently elsewhere on the body at the site of primary infection (e.g. whitlow), particularly at the genitals. Rarely, HSV-1 reactivation can cause encephalitis; however, a third of the cases of HSV-1 encephalitis are associated with HSV-1 primary infection. Primary VZV infection causes varicella (chickenpox) following which latent virus may reactivate decades later to produce herpes zoster (shingles), as well as an increasingly recognized number of subacute, acute and chronic neurological conditions. Following primary infection, both viruses establish a latent infection in neuronal cells in human peripheral ganglia. However, the detailed mechanisms of viral latency and reactivation have yet to be unravelled. In both cases latent viral DNA exists in an 'end-less' state where the ends of the virus genome are joined to form structures consistent with unit length episomes and concatemers, from which viral gene transcription is restricted. In latently infected ganglia, the most abundantly detected HSV-1 RNAs are the spliced products originating from the primary latency associated transcript (LAT). This primary LAT is an 8.3 kb unstable transcript from which two stable (1.5 and 2.0 kb) introns are spliced. Transcripts mapping to 12 VZV genes have been detected in human ganglia removed at autopsy; however, it is difficult to ascribe these as transcripts present during latent infection as early-stage virus reactivation may have transpired in the post-mortem time period in the ganglia. Nonetheless, low-level transcription of VZV ORF63 has been repeatedly detected in multiple ganglia removed as close to death as possible. There is increasing evidence that HSV-1 and VZV latency is epigenetically regulated. In vitro models that permit pathway analysis and identification of both epigenetic modulations and global transcriptional mechanisms of HSV-1 and VZV latency hold much promise for our future understanding in this complex area. This review summarizes the molecular biology of HSV-1 and VZV latency and reactivation, and also presents future directions for study. Received 5 January 2015Accepted 18 March 2015 IntroductionHerpes simplex virus type 1 (HSV-1; human herpesvirus 1) and varicella-zoster virus (VZV; human herpesvirus 3) are human neurotropic alphaherpesviruses usually acquired early in life. Primary HSV-1 infection is usually localized and may be asymptomatic, although it can produce a more widespread systemic infection in neonates and immunocompromised adults, whilst primary VZV infection is systemic and results in childhood varicella (chickenpox). During primary infection, both viruses gain access to neurons most likely through retrograde transport from the site of cutaneous lesion...

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“…Specifically HSV-1 and HSV-2 have been reported to express at least 27 miRNAs (3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13). Analyses of 17 of these miRNAs have shown that they differ in their requirements for synthesis in productively infected cells.…”

mentioning

confidence: 99%

miR-H28 and miR-H29 expressed late in productive infection are exported and restrict HSV-1 replication and spread in recipient cells

Han

Liu

Chen

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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We report on the properties and function of two herpes simplex virus-1 (HSV-1) microRNAs (miRNAs) designated “miR-H28” and “miR-H29.” Both miRNAs accumulate late in productive infection at a time when, for the most part, viral DNA and proteins have been made. Ectopic expression of miRNA mimics in human cells before infection reduced the accumulation of viral mRNAs and proteins, reduced plaque sizes, and at vey low multiplicities of infection reduced viral yields. The specificity of the miRNA mimics was tested in two ways. First, ectopic expression of mimics carrying mutations in the seed sequence was ineffective. Second, in similar tests two viral miRNAs made early in productive infection also had no effect. Both miR-H28 and miR-H29 are exported from infected cells in exosomes. A noteworthy finding is that both miR-H28 and miR-H29 were absent from murine ganglia harboring latent virus but accumulated in ganglia in which the virus was induced to reactivate. The significance of these findings rests on the principle that the transmission of HSV from person to person is by physical contact between the infected tissues of the donor and those of uninfected recipient. Diminished size of primary or recurrent lesions could be predicted to enhance person-to-person transmission. Reduction in the amount of reactivating latent virus would reduce the risk of retrograde transport to the CNS but would not interfere with anterograde transport to a site at or near the site of initial infection.

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Numerous Conserved and Divergent MicroRNAs Expressed by Herpes Simplex Viruses 1 and 2

Cited by 145 publications

References 68 publications

Small RNA Deep Sequencing Identifies MicroRNAs and Other Small Noncoding RNAs from Human Herpesvirus 6B

Small RNA Deep Sequencing Identifies MicroRNAs and Other Small Noncoding RNAs from Human Herpesvirus 6B

A comparison of herpes simplex virus type 1 and varicella-zoster virus latency and reactivation

miR-H28 and miR-H29 expressed late in productive infection are exported and restrict HSV-1 replication and spread in recipient cells

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