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.