Genomic location dictates lytic promoter activity during herpes simplex virus latency

Herpes simplex virus 1 (HSV-1) is a significant pathogen that establishes life-long latent infections with intermittent episodes of resumed disease. In mouse models of HSV infection, persistent low-level lytic gene expression has been detected during latency in the absence of spontaneous reactivation events leading to new virus production. This viral activity during latency has been reported using a sensitive Cre-marking model for several lytic gene promoters placed in one location in the HSV-1 genome. Here we extend these findings in the same model by examining first, the activity of an ectopic lytic gene promoter in other places in the genome and second, whether native promoter activity might be detectable. We found that both for ectopic and native lytic gene promoters, Cre expression during latency was detected in our model, but only when the promoter was located near the ends of the unique long genome segment. This location is significant because it is in close proximity to the region from which latency associated transcripts (LAT) are derived. These results show for the first time that native HSV-1 lytic gene promoters can produce protein products during latency, but that this activity is only detectable when they are located close to the LAT locus.