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The herpes simplex virus (HSV) has a 152 kbp dsDNA encoding probably 84 proteins. The approximate number of ORFs is 94, from which seven are doubled. The most probable number of single copy ORFs is 84 after omitting the two latency associated transcripts (LAT)/ORFs and the putative UL27.5 ORF. The high gene number creates a "crowded" genome with several overlapping transcripts. The unique long (U(L)) segment has at least 10 interposed ORFs, the existence of which was not obvious at first sequence analysis, while the unique short (U(S)) segment has two such genes. The surplus of ORFs causes complex transcription patterns: (1) Transcripts with common initiation signals but different termination; (2) Transcripts with different initiation sites but co-terminal ends; (3) "Nested" transcripts differing at both, the initiation as well as termination signals, having partially collinear sequences. At least three or possibly four ORF (gene) pairs (UL9.5/UL10; UL27/UL27.5; UL43/UL43.5; ICP34.5/ORF P and O) occupy both DNA strands at complementary positions rising anti-sense transcripts expressed by an antagonistic mechanism of mutual exclusion. The anti-sense mRNA mechanism might also operate when either LAT or ICP0 ORFs are expressed during latency assuring the absence of lytic virus replication. In contrast, during productive replication the cascade regulation of gene expression predominates, based on stepwise activation of immediate early (IE), early (E), early late (EL) and late (L) promoters. The promoters of different expression kinetic classes (alpha, beta, gamma-1 and gamma-2) are equipped with different number of cellular transcription factor binding and/or enhancer motifs. Surprisingly, only a few HSV mRNAs are being spliced (ICP0, UL15, US1, US12/ICP47). As reviewed here, the transcription pattern of the great majority of overlapping ORFs within the HSV-1 was quite convincingly elucidated, with exception of the putative UL27.5 gene. The UL27.5 transcript was not identified yet. Since the existence of the UL27.5 gene was based on indirect rather than direct evidence, it needs final confirmation.

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