Abstract
The predicted 80 open reading frames (ORFs) of herpes simplex virus 1 (HSV-1) have been intensively studied for decades. Here, we unravel the complete viral transcriptome and translatome during lytic infection with base-pair resolution by computational integration of multi-omics data. We identify a total of 201 transcripts and 284 ORFs including all known and 46 novel large ORFs. This includes a so far unknown ORF in the locus deleted in the FDA-approved oncolytic virus Imlygic. Multiple transcript isoforms expressed from individual gene loci explain translation of the vast majority of ORFs as well as N-terminal extensions (NTEs) and truncations. We show that NTEs with non-canonical start codons govern the subcellular protein localization and packaging of key viral regulators and structural proteins. We extend the current nomenclature to include all viral gene products and provide a genome browser that visualizes all the obtained data from whole genome to single-nucleotide resolution.
Highlights
The predicted 80 open reading frames (ORFs) of herpes simplex virus 1 (HSV-1) have been intensively studied for decades
It enables quantification of RNA levels as well as identification of 5′ transcript ends by generating a strong enrichment (≈18-fold) of reads that start at the 5′ RNA ends
As virus replication already initiates at 2 h p.i., first virus particles are released at 4 h p.i. and >80% of translational activity in the infected cells is viral at 8 h p.i.11, we restricted our analysis to the first 8 h of infection to reduce the risk of detecting aberrant gene expression in cells with extensive cytopathic disruption of the transcriptional machinery
Summary
The predicted 80 open reading frames (ORFs) of herpes simplex virus 1 (HSV-1) have been intensively studied for decades. For HCMV and KSHV in particular, hundreds of viral gene products were identified These result from extensively regulated usage of alternative transcription and translation start sites throughout lytic infection. These viruses were found to encode hundreds of short ORFs (sORFs) of unknown function. We expanded the number of known of HSV-1 genomic elements to 201 viral transcripts encoding a total of 284 ORFs; including N-terminal peptide extensions and truncations of several classically described viral proteins as well as previously unannotated protein-coding sequences in the loci of genes for major regulatory proteins ICP0 and ICP34.5
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