Fashionably late: Temporal regulation of HSV-1 late gene transcription

Herpes simplex virus type-1 (HSV-1) is an alpha herpesvirus that infects over 60% of the human population [1]. Infection results in a variety of disease manifestations, including cold sores, encephalitis, and keratitis. The HSV-1 genome contains approximately 152 kb of doublestranded DNA and includes over 80 genes [2,3], which are sequentially transcribed by cellular RNA polymerase II (Pol II) [4,5]. Recently, studies using direct RNA sequencing, long-read sequencing, and ribosome profiling have revealed the transcriptional complexity of the HSV-1 genome and demonstrate that the genome actually contains over 200 open reading frames [6– 8]. Viral genes are classified into 4 groups depending on their expression kinetics, including immediate early (α), early (β), leaky-late (γ1), and true late (γ2) genes. HSV-1 DNA replication is a key point in the infectious cycle, as it enables γ2 and amplifies γ1 transcription [9,10]. Below, we discuss the studies that defined the 4 HSV-1 gene classes and examine how viral DNA replication may facilitate a switch to regulate γ (γ1/γ2) gene transcription. Although the HSV-1 gene expression cascade was identified over 40 years ago, high-throughput sequencing approaches continue to reveal new insight into how each gene class is regulated [11–15].