Bovine leukemia virus antisense transcription regulates viral and host genome expression

Abstract

Bovine leukemia virus (BLV) is a deltaretrovirus that naturally infects B-cells of cattle, leading to a widespread lymphoproliferative disease termed enzootic bovine leukosis. In infected individuals, the virus is able to escape from the host immune response by viral silencing while maintaining its replicative and oncogenic potential. The recent discovery of BLV-associated antisense transcripts continuously expressed in both non-malignant and leukemic cells have raised the opportunity to unravel key mechanisms behind viral replication and pathogenesis. The objective of this work is to evaluate the importance of BLV antisense transcription in viral expression and replication, as well as its influence on host genome expression. Data show that mutation of two Sp-1 binding sites inhibits the antisense transcriptional activity of the 3' long terminal repeat (LTR) minimal antisense promoter in vitro. The mutation carried out in the U5 region on a full-length LTR also induces a reduction of antisense transcription, but consequently increases sense transcriptional activity. In the context of a mutated full-length provirus, viral sense and antisense expression are dysregulated in infected animals while proviral loads decrease drastically. Furthermore, the expression of host genes, especially TPPP and HMCN1, is influenced by altered antisense transcriptional activity. Antisense transcription is therefore able to control viral replication by mediating sense transcription and interferes with host genome expression.