Biological and molecular aspects on herpes simplex virus latency.

Latent reactivateable herpes simplex virus (HSV) infections of sensory neurons of peripheral ganglia are most plausibly the source of clinical herpetic recurrences. The establishment of latency is the result of a concert of both viral and cellular factors such as the neuroinvasiveness of the virus, the relative density of receptors binding virus to the nerve cell plasma membrane, the permissiveness of the infection, including the axonal transport of the viral nucleocapsids, and the restriction of virus replication. Several hypotheses have been presented suggesting various mechanisms for the restriction of the HSV infection of the neuron. Thus, for instance the the importance of thymidine kinase negative mutants, hypermethylation of viral DNA and the existence of latency-associated viral genes have been discussed. Activation of the latent infection to a virus-producing lytic infection by means of superinfection with a replication-incompetent mutant is probably a result of genetic complementation. Reactivation by means of superinfection with replication-competent virus seems dependent upon the multiplicity of the superinfecting virus and more than one copy of the virus genome is required for the initiation of the reactivating process. These observations would be consistent with the overcoming of a cellularly controlled restriction of the latent infection. The cellular control of latency which can be impaired mechanically and chemically seems particularly important for the maintenance of latent HSV infection. However, recent observations indicate that reactivation of latent HSV infection is also associated with the expression of a latency-related viral gene (LAT), whereas establishment of the latency apparently is influenced by other properties determined by the genome of the virus, as well as by the capacity of the cell to restrict the lytic infection.