Herpes simplex virus (HSV)

Uncoating of HSV delivers the  linear dsDNA genome into  the  nucleus of the  cell, along  with  an  important protein from  the  tegument, VP16 (also  called  a-TIF). VP16 interacts with Oct-1, a cellular transcription factor that recognizes a specific pro- moter sequence (TAATGARAT, where R is a purine) known as the octamer box. The VP16/ Oct-1 complex preferentially transcribes five crucial HSV immediate early genes (which have promoters containing the octamer box), rather than cellular promoters with the same sequence. With the translation of these five mRNAs (on cytoplasmic ribosomes) into proteins the replication cycle has begun, and subsequent expression of delayed early and late genes is inevitable. The HSV genome encodes for many proteins including several delayed early enzymes involved in the  replication of the  viral genome (e.g. thymidine kinase, DNA polymerase, helicase), which of course must return to the nucleus following their synthesis and  any  post-translational modification (e.g.  Phos- phorylation, glycosylation). Replication of the dsDNA genome occurs in the nucleus and there is much evidence to suggest it is initiated by circularization of the DNA mol- ecule. Terminal redundancy, in the form of direct repeat sequences (the a-sequences), allows the two ends to anneal together forming a circular structure. Replication of the genome is independent of cellular enzymes, and involves the viral DNA polymerase in association with a number of DNA-binding proteins and a helicase enzyme. Replica- tion is thought to be by a unidirectional mechanism known as rolling circle replication, illustrated in Figure. A single replication fork travels around the circular genome many times, giving rise to a long linear ssDNA of multi-genomic length, known as a concatemer, that is subsequently converted to dsDNA. The viral DNA polymerase is the target for a number of antiviral drugs as it is significantly different to the host cell DNA polymerase.

Concomitant with  the  initiation of genome replication is the  expression of the  late viral proteins, including the  structural proteins that will form  the  capsid, enve- lope,  and  tegument, and  nonstructural  scaffolding proteins that allow capsid assembly. Late proteins are usually synthesized to higher levels than earlier proteins, and the proteins involved in HSV capsid assembly must traffic from the cytoplasm into the nucleus.