The miRNA world of polyomaviruses

Abstract

Polyomaviruses are a family of non-enveloped DNA viruses infecting several species, including humans, primates, birds, rodents, bats, horse, cattle, raccoon and sea lion. They typically cause asymptomatic infection and establish latency but can be reactivated under certain conditions causing severe diseases. MicroRNAs (miRNAs) are small non-coding RNAs that play important roles in several cellular processes by binding to and inhibiting the translation of specific mRNA transcripts. In this review, we summarize the current knowledge of microRNAs involved in polyomavirus infection. We review in detail the different viral miRNAs that have been discovered and the role they play in controlling both host and viral protein expression. We also give an overview of the current understanding on how host miRNAs may function in controlling polyomavirus replication, immune evasion and pathogenesis.

Figure 1

Polyomavirus encoded miRNAs. Different genomic locations of the polyomavirus encoded miRNAs have been described, but all of them are targeting the early transcript encoding the Large T-antigen (LTAg) and small T-antigen (stAg). Minor splicing variants of LTAg and MTAg (in MuPyV) are not presented. A, The alpha polyomaviruses JCPyV, BKPyV, SV40 and SA12 encode a miRNA located at the 3′ end of, and antisense to LT. Remark VP4 is included for completeness but has so far only been detected in SV40. B, MCPyV and MuPyV encode a miRNA located at the 5′ end of, and antisense to LT. C, BPCV, a virus that shares distinct characteristics of both the Polyomaviridae and the Papillomaviridae encodes a miRNA located in the second non-coding region (NCR2, indicated in pink) between the 3′ ends of the T-antigens and L1/L2.

Figure 2

Sequences of polyomavirus miRNAs. A, Sequence comparison of the different polyomavirus miRNAs. The mature 5p and 3p miRNAs are indicated in red. Remark that for Bpcv1 and Bpcv2 also a 5p miRNA was observed, but no mapping of the sequence was performed. The sequence that was used for probing of this 5p miRNA is indicated in blue. B, Sequence variants observed in JCPyV. A total of 643 JCPyV nucleotide sequences were retrieved from NCBI and aligned using ClustalW algorithm in BioEdit. Relative abundance (%) of each sequence variant was calculated. JCV-miR-J1 sequence from miRBase V20 was used as reference sequence.

Figure 3

Overview of viral and host miRNA functions related to Polyomavirus infection. Polyomavirus encoded miRNAs exert an autoregulatory role through targeting of LTAg, which plays an essential role in viral replication. This viral miRNA also plays a role in regulating the host immune response by targeting host factors, such as the stress-induced ligand ULBP3, that are essential for recognition of infected cells by the immune system. Host miRNAs can mimic the polyomavirus miRNA, thereby also influencing the expression of LTAg and consequently viral replication, but they might also affect viral protein synthesis by targeting the viral transcripts through binding at the 3′UTR of the viral transcripts. Next to this virus specific role, miRNAs are also shown to play a more general role in the immune response upon viral infection.