The Diverse Roles of microRNAs at the Host⁻Virus Interface

Abstract

MicroRNAs (miRNAs) are small, non-coding RNAs that regulate gene expression at the post-transcriptional level. Through this activity, they are implicated in almost every cellular process investigated to date. Hence, it is not surprising that miRNAs play diverse roles in regulation of viral infections and antiviral responses. Diverse families of DNA and RNA viruses have been shown to take advantage of cellular miRNAs or produce virally encoded miRNAs that alter host or viral gene expression. MiRNA-mediated changes in gene expression have been demonstrated to modulate viral replication, antiviral immune responses, viral latency, and pathogenesis. Interestingly, viruses mediate both canonical and non-canonical interactions with miRNAs to downregulate specific targets or to promote viral genome stability, translation, and/or RNA accumulation. In this review, we focus on recent findings elucidating several key mechanisms employed by diverse virus families, with a focus on miRNAs at the host⁻virus interface during herpesvirus, polyomavirus, retroviruses, pestivirus, and hepacivirus infections.

Keywords: Herpesviruses; hepaciviruses; immune evasion; latency; microRNAs; pestiviruses; polyomaviruses; retroviruses; viral RNA accumulation.

Figure 1

Betapolyomaviruses encode a miRNA in the LTAg region of the genome. (A) Genomic organization of the beta polyomaviruses BKV, JCV and SV40. The genome is divided into an early and late region encoded on opposite strands and separated by a non-coding control region (NCCR). The late strand of the genome encodes three capsid proteins (VP1-3) and two mature miRNAs originating from the same pre-miRNA located at the 3′ end and antisense to the large tumor antigen (LTAg) gene. The polyadenylation sites (pA) are involved in the early-to-late switch. (B) Perfect complementarity of the miRNA to the early viral LTAg mRNA results in direct cleavage and inhibition of LTAg expression to promote latency. The 3p arm of the miRNA directly downregulates expression of the stress-induced ligand ULBP3, contributing to immune evasion. The SV40-encoded miRNA 5p arm mimics hsa-miR-423 and is therefore suggested to contribute to cell transformation by downregulating the tumor suppressor ING-4.

Figure 2

Genome organization of HIV-1 and strategies for suppression of RNA silencing. (A) The proviral DNA genome of HIV-1 encodes three structural genes (gag, pol and env) and several accessory genes (vif, vpr, vpu, tat, rev and nef) which regulate expression of viral proteins and play roles in immune evasion. The genome is flanked by long terminal repeats (LTRs), required for genome integration. Three functional miRNAs are encoded in the LTR region and Nef, which inhibit host and viral gene expression. The LTRs include the transactivation response (TAR) element stem-loop structure which can also be recognized by Dicer and TRBP and processed into TAR-miR-5p and -3p. (B) HIV-1 acts as a suppressor of RNA silencing. The Tat protein inhibits processing of pre-miRNAs by inhibiting Dicer activity. The Rev-response element (RRE) is a structured RNA element that resembles precursor miRNAs, able to compete with pre-miRNAs for TRBP binding.

Figure 3

Genome organization and miRNA binding sites in the BVDV and HCV genomes. The coding regions of BVDV and HCV are flanked by 5′ and 3′ untranslated regions (UTRs) characterized by specific stem-loop (SL) structures. (A) The BVDV genome includes UGA box sequence elements (boxed), a single-stranded (ss) RNA region, let-7 (blue) and miR-17 (green) binding sites. (B) Model of the binding interactions between the BVDV 3′ UTR and miR-17 and let-7. (C) The HCV genome contains two miR-122 binding sites (green) and an IRES element, which includes SLII-IV in the 5′ UTR. The 3′ UTR includes a hypervariable region (HV), a polyU/UC tract of variable length and a highly conserved 3′ X-tail, comprised of SL1-3. MiR-122 binds to two tandem sites in the 5′ UTRs of (D) HCV and (E) GBV-B. The nucleotides binding to the miRNA seed regions are underlined.