Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanisms
ReviewMammalian alphaherpesvirus miRNAs☆
Highlights
► We review the published literature on mammalian alphaherpesviruses and microRNAs. ► So far, five of these viruses are known to express microRNAs. ► The most is known about herpes simplex virus microRNAs. ► Some microRNAs are expressed abundantly during latent infections of sensory neurons. ► Transfection studies suggest some microRNAs might promote latency. ► Overall, we know little about microRNA targets and roles in virus infection.
Section snippets
Introduction: mammalian alphaherpesviruses
Mammalian alphaherpesviruses, which include important human and veterinary pathogens, fall within the order Herpesvirales (herpesviruses). Membership in this order is based, largely, on the morphology of the virion, which includes a core containing a linear double-stranded DNA, which is surrounded by an icosahedral capsid. The capsid is surrounded by the tegument, which is an amorphous proteinaceous material, and that in turn is surrounded by a lipid bilayer envelope [1], [2]. The order
Advantageous features of miRNAs for mammalian alphaherpesviruses
MicroRNAs (miRNA) are ~ 22 nucleotide (nt) small RNA molecules that regulate gene expression of plants, animals and viruses [6], [7]. Briefly, canonical miRNAs arise from longer RNA polymerase II transcripts, called pri-miRNAs, that contain one or more characteristic hairpin structures [8]. The hairpin can be recognized by the nuclear microprocessor complex, which includes the RNAseIII enzyme Drosha and its co-factor DGCR8. Drosha cleaves the hairpin within its stem and relatively proximal to
Discovery of mammalian alphaherpesvirus miRNAs
The first hints that mammalian alphaherpesviruses express miRNAs came from the Tuschl laboratory in 2005 [24]. They applied computational analyses of hairpin structures that might represent pre-miRNAs to predict that HSV-1 and HSV-2 encode seven and six miRNAs, respectively. However, they did not validate these predictions experimentally. Interestingly, these authors also predicted that VZV does not encode any miRNAs. In 2006, Cui et al., using a different computational approach, predicted 13
The prototype simplexvirus, HSV-1, and HSV-2
The prototype simplexvirus, HSV-1 and its very close relative, HSV-2, are ubiquitous human pathogens, widely recognized as the causative agents of cold sores and genital herpes, respectively [1]. Although infections with HSV are usually self-limiting, they can result in severe morbidity and life-threatening diseases, particularly in individuals with undeveloped (e.g. newborns) or compromised (e.g. transplant patients) immunity. HSV-1 is the leading infectious cause of blindness, and the most
Genome location and expression
This review will provide the most detail about HSV miRNAs, because we have more information about them than those from other mammalian alphaherpesviruses, and because they provide comparisons for the miRNAs from the other viruses. To date, sixteen and eighteen miRNAs expressed by HSV-1 and HSV-2, respectively, have been identified (Fig. 1; Table 1). HSV-1 encodes miRNAs named miR-H1–H8 and miR-H11–H18, whereas HSV-2 encodes miR-H2–H7, miR-H9–H13 and miR-H19–H25. This nomenclature was based on
Herpes B virus
Herpes B virus (Macacine herpesvirus 1, BV) is a simplexvirus that is enzootic to macaque monkeys. In its natural host BV causes a self-limiting disease similar to HSV disease in humans [142]. BV is highly prevalent in most macaque colonies, including those colonies used for biomedical research. Unique among herpesviruses, BV can zoonotically infect humans to cause a serious disease; typically causing encephalitis that is 80% fatal if untreated [1]. Even with timely antiviral therapy, 20% of
The prototype varicellovirus, varicella-zoster virus
The prototype varicellovirus is varicella-zoster virus (VZV). VZV is a human pathogen that causes chickenpox (varicella) and shingles (herpes zoster). VZV is highly contagious, and typically infects respiratory mucosa and then quickly spreads to lymphocytes, causing viremia. Subsequently, virus is transported to the skin where it induces the well-recognized rash of chickenpox. These aspects of infection differ greatly from those of HSV and the other simplexviruses. Following these stages of
Bovine herpesvirus 1
BoHV-1 is a varicellovirus that causes economically important diseases in cattle. BoHV-1 is best known for causing a respiratory disease known as infectious rhinotracheitis. BoHV-1 can also cause conjunctivitis, pneumonia, genital disease and abortions, and it is thought to cost the United States cattle industry over $500 million per year [150], [151], [152]. BoHV-1 establishes a latent infection in trigeminal ganglia, and latency is characterized by restricted gene expression [153]; the only
Pseudorabies virus
First described in 1902 by Aujeszky [154], pseudorabies (Aujeszky's disease, mad itch, infectious bulbar paralysis) is an economically important disease of domestic swine, although it has been documented in many other domestic and wildlife species [155]. The causative agent is the varicellovirus, pseudorabies virus (PRV, Suid herpesvirus 1). The virus typically infects via the oro-nasal route and is responsible for a variety of symptoms including abortion and meningoencephalitis. Lethality is
Concluding comments
A major conclusion from this review of mammalian alphaherpesvirus miRNAs is that we know very little about them. The miRNAs encoded by most of these viruses remain to be discovered. The targets for most of the miRNAs that have been discovered remain to be identified. The miRNA–target interactions that have been identified in transfection studies remain to be tested for importance during virus infection. We also know little about how these viruses interact with host miRNAs and the miRNA
Note added in proof
Since the submission of this manuscript, M.A. Amen and A. Griffiths (2011, J. Virol. 85: 7296–7311) have reported the discovery of 12 additional B virus-encoded microRNAs using deep-sequencing of productively infected cells and latently infected monkey trigeminal ganglia. These microRNAs exhibit no sequence conservation with HSV-encoded microRNAs and arise from regions of the genome that exhibit the most sequence differences between B virus and HSV. Expression analyses suggested that individual
Acknowledgments
We gratefully acknowledge funding support from NCRR (P51 RR013986 and R21 RR026287, AG), and NIAID (RO1 AI26126 and PO1 NS35138, IJ and DMC). We thank Martha Kramer for helpful discussions and David Bloom for communicating results ahead of publication.
References (156)
MicroRNAs: genomics, biogenesis mechanisms, and function
Cell
(2004)MicroRNAs: target recognition and regulatory functions
Cell
(2009)- et al.
Prediction of mammalian microRNA targets
Cell
(2003) - et al.
Molecular phylogeny and evolutionary timescale for the family of mammalian herpesviruses
J. Mol. Biol.
(1995) - et al.
Recruitment of activated IRF-3 and CBP/p300 to herpes simplex virus ICP0 nuclear foci: potential role in blocking IFN-beta induction
Virology
(2007) - et al.
Control of TANK-binding kinase 1-mediated signaling by the γ134.5 protein of herpes simplex virus 1
J. Biol. Chem.
(2009) - et al.
HSV-1 ICP34.5 confers neurovirulence by targeting the Beclin 1 autophagy protein
Cell Host Microbe
(2007) - et al.
Characterization of RNA transcripts from herpes simplex virus-1 DNA fragment BamHI-B
Virology
(1989) - et al.
Transcriptional analysis of the herpes simplex virus type 1 region containing the TRL/UL junction
Virology
(1993) - et al.
Identification of a novel 0.7-kb polyadenylated transcript in the LAT promoter region of HSV-1 that is strain specific and may contribute to virulence
Virology
(1999)
Identification of a protein encoded in the herpes simplex virus type 1 latency associated transcript promoter region
Virus Res.
Molecular basis for the recognition of primary microRNAs by the Drosha–DGCR8 complex
Cell
Herpes simplex viruses
The order Herpesvirales
Arch. Virol.
Toward a comprehensive phylogeny for mammalian and avian herpesviruses
J. Virol.
Herpes simplex virus and varicella-zoster virus: why do these human alphaherpesviruses behave so differently from one another?
Rev. Med. Virol.
Varicella-Zoster virus replication, pathogenesis, and management
The role of RNAi and microRNAs in animal virus replication and antiviral immunity
Genes Dev.
MicroRNA maturation: stepwise processing and subcellular localization
EMBO J.
The Microprocessor complex mediates the genesis of microRNAs
Nature
The nuclear RNase III Drosha initiates microRNA processing
Nature
Exportin-5 mediates the nuclear export of pre-microRNAs and short hairpin RNAs
Genes Dev.
A cellular function for the RNA-interference enzyme Dicer in the maturation of the let-7 small temporal RNA
Science
RNA interference is mediated by 21- and 22-nucleotide RNAs
Genes Dev.
Argonaute2 is the catalytic engine of mammalian RNAi
Science
A role for the P-body component GW182 in microRNA function
Nat. Cell Biol.
Most mammalian mRNAs are conserved targets of microRNAs
Genome Res.
Widespread changes in protein synthesis induced by microRNAs
Nature
Mammalian microRNAs predominantly act to decrease target mRNA levels
Nature
The impact of microRNAs on protein output
Nature
Principles of microRNA-target recognition
PLoS Biol.
Identification of microRNAs of the herpesvirus family
Nat. Methods
Prediction and identification of herpes simplex virus 1-encoded microRNAs
J. Virol.
MicroRNAs expressed by herpes simplex virus 1 during latent infection regulate viral mRNAs
Nature
An acutely and latently expressed herpes simplex virus 2 viral microRNA inhibits expression of ICP34.5, a viral neurovirulence factor
Proc. Natl. Acad. Sci. U.S.A.
Novel less-abundant viral microRNAs encoded by herpes simplex virus 2 latency-associated transcript and their roles in regulating ICP34.5 and ICP0 mRNAs
J. Virol.
Discovery of herpes B virus-encoded microRNAs
J. Virol.
Numerous conserved and divergent microRNAs expressed by herpes simplex viruses 1 and 2
J. Virol.
Analysis of human alphaherpesvirus microRNA expression in latently infected human trigeminal ganglia
J. Virol.
Identification of viral microRNAs expressed in human sacral ganglia latently infected with herpes simplex virus 2
J. Virol.
Characterization of microRNAs encoded by the bovine herpesvirus 1 genome
J. Gen. Virol.
Small noncoding RNAs encoded within the bovine herpesvirus 1 latency-related gene can reduce steady-state levels of infected cell protein 0 (bICP0)
J. Virol.
Co-expression of host and viral microRNAs in porcine dendritic cells infected by the Pseudorabies virus
PLoS One
Herpes simplex virus type 2 and syphilis infections with HIV: an evolving synergy in transmission and prevention
Curr. Opin. HIV AIDS
Host cell proteins bind to the cis-acting site required for virion-mediated induction of herpes simplex virus 1 alpha genes
Proc. Natl. Acad. Sci. U.S.A.
Binding of the virion protein mediating alpha gene induction in herpes simplex virus 1-infected cells to its cis site requires cellular proteins
Proc. Natl. Acad. Sci. U. S. A.
Differentiation and DNA contact points of host proteins binding at the cis site for virion-mediated induction of alpha genes of herpes simplex virus 1
J. Virol.
Temporal regulation of herpes simplex virus type 1 transcription: location of transcripts on the viral genome
Cell
Control of herpes simplex virus type 1 mRNA synthesis in cells infected with wild type virus or the temperature sensitive mutant tsK
J. Virol.
A herpes simplex virus type 1 function continuously required for early and late virus RNA synthesis
Nature
Cited by (27)
Viral miRNA regulation of host gene expression
2023, Seminars in Cell and Developmental BiologyCitation Excerpt :Collectively, these data suggest that viral miRNAs can be used as biomarkers for prognosis of disease states. Extensive research has established that most viruses encode miRNAs that target at least one viral gene [117,193,232–238]. During lytic infection, viral miRNAs are often expressed with early or late kinetics, when many viral genes are already highly expressed, suggesting that viral miRNAs act to regulate viral gene expression only later in infection.
MicroRNA profiling in the bursae of Marek's disease virus-infected resistant and susceptible chicken lines
2020, GenomicsCitation Excerpt :The majority of the virally encoded miRNAs identified so far belongs to herpesviruses [27,28]. Using small coding capacity and being non-immunogenic, miRNAs are ideally suited as regulatory molecules to be exploited by viruses for replication and evasion of cellular defense mechanisms [29,30]. MDV, also a member of the Herpesviridae family and the causative agent of acute T cell lymphomas and solid visceral tumors in chickens, encodes a panel of miRNAs clustering within Meq oncogene flanking sites and latency-associated transcripts (LAT) regions [31,32].
Herpes simplex virus 1 miRNA sequence variations in latently infected human trigeminal ganglia
2018, Virus ResearchCitation Excerpt :In fact, HSV-1 has been shown to encode at least 20 miRNAs (miR-H1 – H29), some of which are conserved in HSV-2 (Han et al., 2016; Jurak et al., 2010; Munson and Burch, 2012; Umbach et al., 2008, 2009). The genomic loci of most of these miRNAs are located within the inverted repeat of the genome and within the LAT locus (Jurak et al., 2011). During latency the expression of these miRNAs strongly depends on the activity of the LAT promoter (LAP), indicating that the 8.3 kb transcript is also the primary transcript for the biogenesis of several miRNAs (Kramer et al., 2011).
HSV1 latent transcription and non-coding RNA: A critical retrospective
2017, Journal of NeuroimmunologyCitation Excerpt :In addition to the multiple long and small non-coding RNAs described above, HSV1 employs a collection of miRNAs. The use of small non-coding RNAs, including miRNAs, by viruses as a means of interacting with the host has a documented history (reviewed in Umbach and Cullen, 2009, or more specifically to the Alphaherpesvirinae subfamily in Jurak et al., 2011). The canonical biogenesis of miRNA is, in brief, as follows: RNA containing the precursor miRNAs are processed nuclearly by the enyzme Drosha, exported as an RNA hairpin, and subsequently processed cytoplasmically by Dicer to form approximately 22 nucleotide RNA duplexes, from which one strand is incorporated into the RNA-induced silencing complex (RISC).
A host MicroRNA brokers truce with HSV-1
2014, Cell Host and MicrobeCitation Excerpt :Consistent with this hypothesis, members of both the Herpesviridae and Polyomaviridae families encode autoregulatory miRNAs that control expression of their lytic genes. For example, the LAT locus of HSV-1 encodes several miRNAs (Umbach et al., 2008; Jurak et al., 2011), which have been linked to downregulation of the IE genes ICP0 and ICP34.5 (Umbach et al., 2008). Thus, it is firmly established that diverse viruses can use miRNAs to regulate the expression of their own genes—a potential factor in both establishing and maintaining latent infections.
Viral MicroRNAs in Herpes Simplex Virus 1 Pathobiology
2024, Current Pharmaceutical Design
- ☆
This article is part of a Special Issue entitled: “MicroRNAs in viral gene regulation”.