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Molecular basis of HSV latency and reactivation.


Human Herpesviruses: Biology, Therapy, and Immunoprophylaxis. Cambridge: Cambridge University Press; 2007. Chapter 33.


Primary infection with HSV-1 or HSV-2 results in productive replication of the virus at the site of infection, following the pattern of gene expression described elsewhere in this volume. During this initial phase, virus enters sensory neurons via their termini and retrograde transport takes the genome to the neuronal nuclei in the sensory ganglia that innervate the infected dermatome. At early times after infection, virus replication occurs in ganglionic neurons but within a few days no virus can be detected. The genome, however, persists in neurons in a latent state from which it reactivates periodically to resume replication and produce infectious virus. This reactivation event may be “spontaneous” but is generally thought to be provoked by stress stimuli that act on the neuron, or at a peripheral site innervated by the infected ganglion, or systemically. Three phases of latency are recognized. Establishment occurs during the period following primary infection, and although virus replication can be detected in a proportion of neurons during this phase, the initiation and normal progression of productive infection and cell death is arrested in those neurons destined to become latently infected. Unravelling the way in which the seemingly inexorable progression of the gene expression program is blocked constitutes a major challenge for the molecular virologist. The maintenance phase of latency is characterized by the lifelong retention of the HSV genome in a silent state, characterized by repression of all viral lytic genes. One region, encoding the latency-associated transcripts (LATs), remains active during latency. Questions relating to the maintenance of the latent state focus on the structure of the genome, the mechanisms that silence it, and the specific properties of the LAT transcription unit that enable it to remain active. During the reactivation phase the silent genome responds to cellular signals that provoke the resumption of viral gene expression. The molecular basis for this dramatic functional reversal is poorly understood and is the subject of considerable research effort. In view of the specific association of LAT with the latent state, questions concerning the role of this transcript pervade all aspects of latency.

Copyright © Cambridge University Press 2007.

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