Until recently, scientists had assumed that there are about 80 open reading frames (ORFs) in the genome of herpes simplex virus 1 (HSV-1). Now researchers at the Julius-Maximilians-Universität (JMU) Würzburg in Bavaria, Germany, and colleagues at other institutions have shown that there are a lot more—namely 284 ORFs. These are translated from hundreds of novel viral transcripts, which have been identified by the team in an article “Integrative functional genomics decodes herpes simplex virus 1” in Nature Communications.

“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,” write the investigators.

“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.”

“The new findings now make it possible to study the individual genes of the virus much more precisely than before,” says Lars Dölken, PhD, head of the JMU Chair of Virology. He was in charge of this project together with Florian Erhard, PhD, JMU junior professor of systems virology. The research team used a broad spectrum of the latest systems biology methods for the study. In addition to JMU, the Max Delbrück Center for Molecular Medicine in Berlin, the University of Cambridge in England, and Ludwig-Maximilians-Universität of Munich were involved.

The data are not only important for a better understanding of the virus itself, continues Dölken, but they also have concrete implications, for example for the development of HSV-1-based oncolytic viruses, which are used in immunological therapies of certain tumor diseases, such as malignant melanoma.

Herpes simplex viruses of type 1 (HSV-1) are known to many people as the cause of cold sores. An infection with this virus can also have serious consequences. For example, HSV-1 can cause life-threatening pneumonia in patients in intensive care units. And in healthy people, it can cause encephalitis, which can lead to permanent brain damage. Once infected with the virus, a person will retain it for the rest of his or her life: herpes viruses permanently nestle in body cells. Only under special circumstances, such as a weakened immune system, do they become active again.

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