Focal transcriptional activity of murine cytomegalovirus during latency inthe lungs

Interstitial pneumonia is a frequent and critical manifestation of human cy tomegalovirus (CMV) disease in immunocompromised patients, in particular in recipients of bone marrow transplantation. Previous work in the murine CMV infection model has identified the lungs as a major organ site of CMV late ncy and recurrence. It was open to question whether the viral genome is tra nscriptionally silent or active during latency. Transcription could be late ncy associated and thus be part of the latency phenotype, Alternatively, tr anscriptional activity could reflect episodes of reactivation. We demonstra te here that transcription of the immediate-early (IE) transcription unit i e1-ie3 selectively generates iel-specific transcripts during latency. Notab ly, while the latent viral DNA was found to be evenly distributed in the lu ngs, transcription was focal and randomly distributed. This finding indicat es that IE transcription is not a feature inherent to murine CMV latency bu t rather reflects foci of primordial reactivation, However, this reactivati on did not initiate productive infection, since ie3 gene mRNA specifying th e essential transactivator IE3 of murine CMV early gene expression was not detectable. Accordingly, transcripts encoding gB were absent during latency , By contrast, during induced virus recurrence, IE-phase transcription swit ched from focal to generalized and ic3-specific transcripts were generated, These data imply that latency and recurrence are regulated not only at the IE promoter-enhancer and that there exists an additional checkpoint at the level of precursor RNA splicing. We propose that focal transcription refle cts random episodes of nonproductive reactivation that get terminated befor e IE3 is expressed and ignites the productive cycle.