Replication of the herpes simplex virus genome: does it really go around in circles?

Abstract

Herpes simplex virus type 1 (HSV-1) is the prototype and best-studied virus of the α-herpesvirus group. HSV-1 undergoes a rapid productive replication cycle in host epithelial cells in vivo and in susceptible cultured cells in vitro . However, HSV-1 is also neurotropic and establishes life-long latent infections in the sensory neurons of the host, where the genome is in a nonreplicating chromatin-associated state (1), and viral gene expression is largely repressed (2). Although the mechanisms for the establishment of latency are poorly understood, reactivation requires an immediate early protein, termed ICP0, which is also required for efficient initiation of lytic infection (3–7). The 152-kb linear double-stranded HSV-1 genome is divided into long and short regions of unique sequences, termed UL and US, which are bounded by regions of inverted repeats, termed internal repeats. The genome termini are bounded by regions of direct repeats, termed terminal repeats (Fig. 1). Furthermore, the HSV-1 genome undergoes inversions that result from recombination events mediated by the viral DNA replication machinery, which yield four genomic isomers in equimolar amounts (8, 9). In vivo , the HSV-1 genome has been found to exist in at least three different states: linear, circular, and concatemeric. In the virion, genomes are linear, but within hours after infection, end joining has been found to occur, resulting in ``endless genomes'' that have been interpreted to represent circles (10–12). Although the mechanism of genome circularization has not been established, one model predicts that circularization may involve recombination of the terminal repeats, resulting in a θ replication mode for the initial round of replication (13), providing the template for a rolling circle mode of replication (14). Thus, genome circularization has been thought to be a prerequisite for viral DNA replication, although …