Bovine leukemia virus AS1 transcription in sheep coincides with infection, host immune responses and lymphoma.

Bovine leukemia virus (BLV) causes a long subclinical infection and can result in B-cell leukemia/lymphoma. However, the in vivo relationship between expression of the BLV antisense transcript AS1 and the sense transcripts, tax/rex or env, and how these relate to host immune responses and lymphoma onset, remains unclear. We used an experimental model of sheep BLV infection to analyze whole blood longitudinally in the proximal (up to 40 days post-inoculation) and late phase (starting 6 months prior to lymphoma onset) of infection, up to and including lymphoma onset. We observed a stereotypical pattern of viral transcript expression, starting with tax/rex and env, followed by AS1-S/L transcription. Proviral load (PVL) in the blood and percentage of infected cells were elevated from 10 to 20 days post-inoculation and coincided roughly with AS1-S/L expression, and BLV-antibody induction occurred soon thereafter. In the late phase of infection, tax/rex was constitutively expressed at 6 months before onset and decreased as lymphoma onset approached. In contrast, PVL, the proportion of infected cells, AS1-S/L, and expression of the anti-inflammatory cytokine IL-10 increased at lymphoma onset, while IFN-γ decreased. These findings indicate that sense (tax/rex) and antisense (AS1-S/L) transcription are differentially regulated in BLV-infected sheep, with the increased viral burden at lymphoma onset being associated with monoclonal expansion of circulating BLV-infected cells. In particular, the development of lymphoma appears to be associated with AS1-S/L transcription and changes in immune indicators consistent with reduced T-cell-mediated immune activity.