UL30 and OriS located in a pair near the RS. As the L and S segments can be assembled in any direction, they can be inverted relative to each other freely, forming various linear isomers. Gene expression HSV genes are expressed in 3 temporal classes: immediate early (IE or α), early (E or ß) and late (γ) genes. However, the progression of viral gene expression is rather gradual than in clearly distinct stages. Immediate early genes are transcribed right after infection and their gene products activate transcription of the early genes. Early gene products help to replicate the viral DNA. Viral DNA replication, in turn, stimulates the expression of the late genes, encoding the structural proteins. Transcription of the immediate early (IE) genes begins right after virus DNA enters the nucleus. All virus genes are transcribed by host RNA polymerase II. Although host proteins are sufficient for virus transcription, viral proteins are necessary for the transcription of certain genes. 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. Four