Persistent Infection of Simian Foamy Virus Derived from the Japanese Macaque Leads to the High-Level Expression of microRNA that Resembles the miR-1 microRNA Precursor Family

Abstract

MicroRNAs (miRNAs) are a group of small non-coding RNAs that suppress the expression of target mRNAs. The seed sequence of miRNA plays a crucial role in recognizing the 3′-untranslated region of the target mRNA. Cells infected with a simian foamy virus (SFV) isolated from an African green monkey (Chlorocebus aethiops) (SFVcae) showed high expression levels of viral miRNAs encoded in the long terminal repeat of SFVcae. In the present study, we investigated the roles and expression of miRNAs derived from an SFV isolated from a Japanese macaque (Macaca fuscata) (SFVmfu) using next-generation sequencing technologies. The results obtained showed that SFVmfu also expressed viral miRNAs; however, the seed sequences of most miRNAs derived from SFVmfu differed from those reported previously from SFVcae. Cells persistently infected with SFVmfu strongly expressed an miRNA with the same seed sequence as the miR-1 microRNA precursor family. Luciferase reporter assays indicated that this miRNA down-regulates the expression of adenylyl cyclaseassociated protein 1, which is up-regulated in several solid tumors. The present results suggest that SFVmfu utilizes viral miRNAs to establish long-term coexistence with the Japanese macaque.

Functional Analyses of Bovine Foamy Virus-Encoded miRNAs Reveal the Importance of a Defined miRNA for Virus Replication and Host–Virus Interaction

“…The issue whether HIV expresses miRNAs is controversial: HIV miRNAs are expressed at very low levels and these short RNAs often display deviant features such as their size, as discussed by Balasubramaniam [6]. In clear contrast, canonical miRNAs have been detected at considerable to even very high levels in cells infected with bovine leukemia virus (BLV, [7]), bovine foamy virus (BFV, [8]), and simian foamy virus of African green monkeys (SFV agm , [9]) and Japanese macaques (SFV cae , [10]).…”

“…Expression of the primary miRNAs (pri-miRNAs) of BLV, BFV, SFV agm , and SFV cae is directed by unique short transcripts generated by RNA Pol III [7][8][9][10]. While in BLV the pri-miRNAs consist of individual, single stem-loop structures, the single pri-miRNA species of BFV and some of those from SFV agm and SFV cae consist of two closely spaced stem-loops with an overall dumbbell structure [7][8][9][10]13]. In SFV agm and SFV cae , additional pri-miRNAs may be similar to those of BLV consisting of only a single stem-loop [9,10,13].…”

“…While in BLV the pri-miRNAs consist of individual, single stem-loop structures, the single pri-miRNA species of BFV and some of those from SFV agm and SFV cae consist of two closely spaced stem-loops with an overall dumbbell structure [7][8][9][10]13]. In SFV agm and SFV cae , additional pri-miRNAs may be similar to those of BLV consisting of only a single stem-loop [9,10,13]. The single-and double stem-loop RNA Pol III pri-miRNAs of FVs as summarized by Materniak et al, 2019 [13] may be the end-product of complex evolutionary processes that may have been primarily shaped by the limited genetic coding capacity of retro-and spumaviral genomes.…”

“…To our knowledge, an RNA Pol III-driven dumbbell-shaped pri-miRNA is a unique feature of BFV, SFV agm , and SFV cae with unambiguous experimental data on the expression (abundance), processing, and potential utilization for translational purposes [8][9][10]13,19]. For both SFVs, target gene prediction has been performed and some of the targets have been validated based on reporter constructs in heterologous cells [9,10].…”

“…To our knowledge, an RNA Pol III-driven dumbbell-shaped pri-miRNA is a unique feature of BFV, SFV agm , and SFV cae with unambiguous experimental data on the expression (abundance), processing, and potential utilization for translational purposes [8][9][10]13,19]. For both SFVs, target gene prediction has been performed and some of the targets have been validated based on reporter constructs in heterologous cells [9,10]. Since BFV has only a single dumbbell-shaped pri-miRNA and correspondingly only a single expression cassette, it appears to be a comparably simple and easy to engineer model compared to SFV agm and SFV cae with a less defined mix of single-and double-stem-loop structures [8][9][10]13].…”