two or more viruses per host cell), MR is observed. Enhanced survival of HSV-1 due to MR occurs upon exposure to different DNA damaging agents, including methyl methanesulfonate, trimethylpsoralen (which causes inter-strand DNA cross-links), and UV light. After treatment of genetically marked HSV with trimethylpsoralen, recombination between the marked viruses increases, suggesting that trimethylpsoralen damage stimulates recombination. MR of HSV appears to partially depend on the host cell recombinational repair machinery since skin fibroblast cells defective in a component of this machinery (i.e. cells from Blooms syndrome patients) are deficient in MR.These observations suggest that MR in HSV infections involves genetic recombination between damaged viral genomes resulting in production of viable progeny viruses. HSV-1, upon infecting host cells, induces inflammation and oxidative stress. Thus it appears that the HSV genome may be subjected to oxidative DNA damage during infection, and that MR may enhance viral survival and virulence under these conditions. Use as an anti-cancer agent
Modified Herpes simplex virus is considered as a potential therapy for cancer and has been extensively clinically tested to assess its oncolytic (cancer killing) ability. Interim overall survival data from Amgens phase 3 trial of a genetically attenuated herpes virus suggests efficacy against melanoma. Use in neuronal connection tracing
Herpes simplex virus is also used as a transneuronal tracer defining connections among neurons by virtue of traversing synapses. Other related outcomes
HSV-2 the most common cause of Mollarets meningitis. HSV-1 can lead to potentially fatal cases of herpes simplex encephalitis.
For instance, VP16 plays an important role in IE transcription and the virus particle apparently brings it into the host cell, so that it does not need to be produced first. Similarly, the IE proteins RS1 (ICP4), UL54 (ICP27), and ICP0 promote the transcription of the early (E) genes. Like IE genes, early gene promoters contain binding sites for cellular transcription factors. One early protein, ICP8, is necessary for both transcription of late genes and DNA replication.Later in the life cycle of HSV, expression of immediate early and early genes is shut down. This is mediated by specific virus proteins, e.g. ICP4, which represses itself by binding to elements in its own promoter. As a consequence, the down-regulation of ICP4 levels leads to a reduction of early and late gene expression, as ICP4 is important for both.Importantly, HSV shuts down host cell RNA, DNA and protein synthesis to direct cellular resources to virus production. First, the virus  protein vhs induces the degradation of existing mRNAs early in infection. Other viral genes impede cellular transcription and translation. For instance, ICP27 inhibits RNA splicing, so that virus mRNAs (which are usually not spliced) gain an advantage over host mRNAs. Finally,  virus proteins destabilize certain cellular proteins involved in the host cell cycle, so that both cell division and host cell DNA replication disturbed in favor of virus replication. Evolution
The herpes simplex 1 genomes can be classified into six clades.