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  • Review Article
  • Published:

MicroRNAs: expression, avoidance and subversion by vertebrate viruses

Nature Reviews Microbiology volume 4, pages 651–659 (2006)Cite this article

Key Points

  • The genomes of some vertebrate viruses encode small non-protein-coding transcripts that can be processed by the host-cell RNA interference (RNAi) pathway to yield mature 21-nucleotide microRNAs (miRNAs). miRNAs were first discovered in Caenorhabditis elegans, and the host-cell machinery that synthesizes miRNAs has been characterized.

  • Several DNA viruses encode miRNAs. Some members of the herpesvirus family encode miRNAs that are produced during both lytic and latent phases of the viral life cycle. In herpes simplex virus type 1, the latency-associated transcript LAT (which is non-protein-coding) is processed to yield an miRNA — miR-LAT — that downregulates the expression of genes involved in transforming growth factor-β-mediated signalling. This, in turn, protects latently infected neurons from undergoing apoptosis.

  • An miRNA that is present in the simian-virus-40 genome downregulates the amount of mRNA that encodes the viral tumour antigens. This renders infected cells less susceptible to lysis by cytotoxic T lymphocytes that target viral tumour antigens.

  • Unlike DNA viruses, sequences that encode miRNAs have not been found in RNA viruses. This is thought to result from the replication strategy of RNA viruses, in which full-length genomic RNAs are required to produce progeny viral RNAs. In addition, the genomes of RNA viruses are usually localized to the host-cell cytoplasm and therefore cannot use nuclear components of the RNAi machinery.

  • Several viral genomes interact with cellular miRNAs. Importantly, studies on hepatitis C virus have revealed that a liver-specific miRNA known as miR-122 is recruited for the selective amplification of viral RNAs in cultured liver cells. This finding indicates the potential of using cellular miRNAs as targets for antiviral therapeutics.

Abstract

MicroRNAs (miRNAs), which can be expressed in a cell-type and tissue-specific manner, can influence the activities of genes that control cell growth and differentiation. Viruses often have clear tissue tropisms, raising the possibility that cellular miRNAs might modulate their pathogenesis. In this Review, we discuss recent findings that some vertebrate viruses either encode miRNAs or subvert cellular miRNAs, and that these miRNAs participate in both the infectious and the latent phase of the viral life cycle.

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Figure 1: MicroRNA (miRNA) biogenesis pathway.
Figure 2: Simian virus 40 (SV40)-encoded microRNAs (miRNAs) reduce susceptibility to lysis by cytotoxic T lymphocytes (CTLs).
Figure 3: The diverse functions of adenovirus virus-associated 1 (VA1) RNA.
Figure 4: Interaction of cellular microRNAs (miRNAs) with viral genomes.
Figure 5: Cholesterol-biosynthesis-pathway genes that are upregulated by miR-122.

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Acknowledgements

Work in the authors' laboratory was supported by grants from the National Institutes of Health (USA), the Alberta Heritage Foundation for Medical Research (Canada) (to K.L.N.) and the Damon Runyon Cancer Research Foundation (USA) (to K.A.W.).

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  1. Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, 94301, California, USA

    Peter Sarnow, Catherine L. Jopling, Kara L. Norman, Sylvia Schütz & Karen A. Wehner

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DATABASES

Entrez Genome

EBV

HCV

HHV3

HHV6

HHV7

HSV-1

KSHV

MHV68

Glossary

MicroRNA molecules

(miRNAs). Small RNAs produced by Drosha- andDicer-mediated cleavage of RNA-hairpin structures that are encoded in cellular and viral genomes.

Endoribonuclease III enzymes

A large family of endoribonucleases, including Drosha and Dicer, that cleave double-stranded RNAs leaving monophosphates at the 5′ terminus and hydroxyl groups at the 3′ terminus.

Argonaute family

A family of proteins that contain the domain PAZ (named after a domain that is present in the proteins Piwi, Argonaute and ZWILLE) and the domain PIWI (named after a domain in the protein Piwi). Mammals have four AGO-subfamily members (AGO1, AGO2, AGO3 and AGO4), each of which might be a component of an RNA-induced silencing complex. Only AGO2 has been shown to induce cleavage of target RNA.

Stage III latency

Three forms of latent infection — latency type I, type II and type III — have been described for B cells that are infected with Epstein–Barr virus. Latency types are characterized by the expression of specific sets of viral proteins.

Viral tumour antigens

Proteins that are encoded by viral genes and can cause cellular transformation. These proteins can, however, also be essential for replication of the viral genome.

2′-O-methyl-antisense oligonucleotides

Oligonucleotides that are synthesized to be complementary to a target microRNA and inhibit its activity.

Small interfering RNA molecules

(siRNAs). RNAs that are produced by Dicer-mediated cleavage of long double-stranded RNA that has been formed by base pairing between two independent transcripts.

Antagomirs

A new class of chemically modified, cholesterol-conjugated single-stranded RNA analogues that are complementary to microRNAs. The design of these molecules is an extension of the 2′-O-methyl-antisense-oligonucleotide concept, and their function is similar to that of 2′-O-methoxyethyl phosphorothioate-modified antisense oligonucleotides. These types of molecule can be used to silence specific microRNAs in vivo and could provide a way to silence microRNAs in individuals with particular diseases.

Hepatic steatosis

Lipid-droplet accumulation in liver cells. It can occur as a result of abnormal fatty-acid metabolism, and is associated with several diseases and conditions, including hepatitis C and obesity.

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Sarnow, P., Jopling, C., Norman, K. et al. MicroRNAs: expression, avoidance and subversion by vertebrate viruses. Nat Rev Microbiol 4, 651–659 (2006). https://doi.org/10.1038/nrmicro1473

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