Viruses, microRNAs, and host interactions

Abstract

One of the most significant recent advances in biomedical research has been the discovery of the approximately 22-nt-long class of noncoding RNAs designated microRNAs (miRNAs). These regulatory RNAs provide a unique level of posttranscriptional gene regulation that modulates a range of fundamental cellular processes. Several viruses, especially herpesviruses, also encode miRNAs, and over 200 viral miRNAs have now been identified. Current evidence indicates that viruses use these miRNAs to manipulate both cellular and viral gene expression. Furthermore, viral infection can exert a profound impact on the cellular miRNA expression profile, and several RNA viruses have been reported to interact directly with cellular miRNAs and/or to use these miRNAs to augment their replication potential. Here we discuss our current knowledge of viral miRNAs and virally influenced cellular miRNAs and their relationship to viral infection.

Figure 1. miRNA biogenesis pathways

Pre-miRNAs can be generated (i) by Drosha/DGCR8 cleavage of long pri-miRNAs, or independent of Drosha/DGCR8, (ii) following debranching of lariat-structures known as miRtrons, (iii) through alternative folding of tRNAs or snoRNAs, or (iv) by tRNAse Z cleavage of pri-miRNAs containing tRNA-like structures linked to pre-miRNA stem-loops. Once exported to the cytoplasm, pre-miRNAs are cleaved by Dicer to generate a miRNA duplex, one strand of which is incorporated into RISC to target mRNAs.

Figure 2. Locations of the viral pre-miRNAs encoded by human herpesviruses

Both α and γ herpesvirus pre-miRNAs primarily reside in latency-associated clusters (HSV-1, HSV-2, EBV, and KSHV) while hCMV miRNAs are scattered throughout the genome.

Figure 3. Viral miRNA targets

Viral miRNAs target perfectly complementary viral mRNAs as well as imperfectly complementary viral and/or cellular mRNAs. Viral miRNA targets can be further divided into functional categories. Some targets have roles in lytic transactivation while others are involved in cellular growth, stress, or immune activation.