Two alternative models of HSV-1 gene regulation. A. Genetic organization of the HSV-1 genome. The long-repeated (RL) and short-repeated (RS) regions of the HSV-1 genome regulate expression of 4 of 5 immediate-early (IE) genes (white arrows). The unique long (UL) and unique short (US) regions contain most of the early (E) and late (L) genes (yellow and red arrows). The 15 kb RL and RS regions include a 2 kb recombinogenic 'joint' sequence, the ICP34.5 gene (red arrow), and the LAT and L/ST genes which are repressed during productive replication (black arrows). B. The current model of HSV-1 gene regulation  describes a cascade of IE → E → L gene expression. C. The proposed Checkpoint model predicts that HSV-1 gene expression proceeds by the accepted cascade, but that viral gene expression can be blocked during viral IE mRNA synthesis if ICP0 is not synthesized (Checkpoint 1) or can be blocked during viral L protein synthesis if ICP34.5 is not synthesized (Checkpoint 2).