A complex network of transcription factors and epigenetic regulators involved in bovine leukemia virus transcriptional regulation

Bovine Leukemia Virus (BLV) is the etiological agent of enzootic bovine leukosis, a disease characterized by the neoplastic proliferation of B cells in cattle. While most European countries have introduced efficient eradication programs, BLV is still present worldwide and no treatment is available. A major feature of BLV infection is the viral latency, which enables the escape from the host immune system, the maintenance of a persistent infection and ultimately the tumoral development. BLV latency is a multifactorial phenomenon resulting in the silencing of viral genes due to genetic and epigenetic repressions of the viral promoter located in the 5MODIFIER LETTER PRIME Long Terminal Repeat (5MODIFIER LETTER PRIMELTR). However, viral miRNAs and antisense transcripts are expressed from two different proviral regions, respectively the miRNA cluster and the 3MODIFIER LETTER PRIMELTR. These latter transcripts are expressed despite the viral latency affecting the 5MODIFIER LETTER PRIMELTR and are increasingly considered to take part in tumoral development. In the present review, we provide a summary of the experimental evidence that has enabled to characterize the molecular mechanisms regulating each of the three BLV transcriptional units, either through cis-regulatory elements or through epigenetic modifications. Additionally, we describe the recently identified BLV miRNAs and antisense transcripts and their implications in BLV-induced tumorigenesis. Finally, we discuss the relevance of BLV as an experimental model for the closely related human T-lymphotropic virus HTLV-1.

Automated summary

Bovine Leukemia Virus (BLV) is the cause of enzootic bovine leukosis, which is characterized by the proliferation of B cells in cattle. BLV has the ability to remain dormant in the host, evade the immune system, and promote tumor development. This review summarizes the molecular mechanisms regulating BLV transcription units, including cis-regulatory elements and epigenetic modifications. It also discusses the role of BLV miRNAs and antisense transcripts in tumorigenesis and the relevance of BLV as a model for studying HTLV-1.