Herpes Simplex Virus Fundamentals Lifelong Latency Punctuated By Episodes Of Productive Growth

"O 'er ladies lips, who straight on kisses dream, which oft the angry Mab with blisters plagues, because their breaths with sweetmeats tainted are."

- William Shakespeare, Romeo and Juliet, circa 1595.

Following infection of oral epithelial cells in its human host, HSV-1 invades axons and travels to the nuclei of sensory neurons that innervate this epithelia. Here, the virus establishes a latent infection, characterized by a restricted pattern of viral gene expression, the assembly of the viral genome into a regular chromatin structure, and its maintenance as a circular extrachromosomal element (2). Latency, therefore, results in the permanent colonization of the host by the virus, and the severely limited expression of viral genes functions to shield the virus from host defenses.

In response to a variety of stimuli, these latent infections "reactivate," resulting in episodes of productive viral growth characterized by expression of over 80 viral open reading frames (ORFs) distributed among two unique, single copy segments or within multiple repetitive loci of the large HSV-1 DNA genome. Activation of the productive or lytic gene expression program results in the production of viral particles and the eventual death of the infected cell. Distinct mRNA populations accumulate at discrete times in the productive replication cycle, resulting in the differential expression of viral genes in what has been termed a cascade pattern (see Fig. 1) (2). The process is

Fig. 1. The HSV-1 productive or lytic replication cycle. Following fusion of the virion envelope with the host plasma membrane, the viral nucleocapsid is deposited into the cytosol along with numerous proteins contained within the virus particle, one of which is the virus encoded transcription factor VP16. After the nucleocapsid docks at the nuclear membrane, viral DNA translocates through the nuclear pore into the nucleus. Transcription from 5 immediate early (IE or a) viral genes commences once the cellular transcription machinery is recruited to the promoters by VP16. Several IE gene products (ICP 4,0,22, and 27) are important for the subsequent expression of the second class of viral genes, the early genes, and return to the nucleus after being synthesized in the cytosol. Early (E or P) mRNAs predominately encode proteins involved in nucleotide metabolism and DNA synthesis. Replicating viral DNA accumulates as a large concatamer in the nucleus, where multiple genome segments are joined end to end, and is subsequently processed into unit length genomes concomitant with packaging into newly assembled nucleocapsids. In addition, DNA synthesis marks the transition from the early phase of the lifecycle to the late or y2 phase, and is associated with an increase in late y2 mRNAs. Late genes (L or y) encode virion structural proteins along with virion components required for subsequent rounds of infection (i.e., VP16). Once assembled in the nucleus, capsids acquire an envelope by budding from the nuclear membrane. One proposed pathway for HSV-1 egress suggests enveloped capsids between the inner and outer leaflets of the nuclear membrane fuse with the outer nuclear membrane, releasing unenveloped capsids into the perinuclear region. These capsids transit through the cytosol and are thought to acquire other virion protein components and their final lipid envelope by budding into a post-golgi compartment prior to exiting the cell.

initiated by VP16, a transcription factor carried within the viral particle that recruits cellular transcription factors along with the RNA polymerase II holoenzyme to the promoters of five viral immediate-early (IE or a) genes. Whereas one of these IE gene products dampens the host immune response by inhibiting the presentation of peptide antigens in conjunction with major histocompatability complex (MHC) class I molecules, the remaining four IE proteins are important for the subsequent expression of the next class of viral genes, the early or P genes. Viral early polypeptides primarily encode functions required for nucleotide metabolism and viral DNA synthesis, the initiation of which signals entry into the final late or y phase of the viral life cycle. Two classes of late genes have been identified based upon their transcription in the presence of viral DNA synthesis inhibitors. Whereas transcription of a subset of y genes, the y2 class, requires viral DNA synthesis, expression of 71 genes is not completely dependent upon viral DNA replication and is only modestly reduced in the presence of inhibitors. Included among the late gene products are polypeptides critical for assembling infectious virus, virion components that function following entry but before IE gene expression, and proteins that regulate the host response to infection. Reactivation of a latent infection in a sensory neuron results in antereograde transport of viral progeny back to the portal of entry followed by the ensuing infection of epithelial cells, mobilization of the cellular immune response, and the formation of a fever blister or cold sore. Rarely, HSV-1 can enter and replicate within the central nervous system (CNS), causing encephalitis.

Although many HSV-1 genes are required for the virus to productively infect an established cultured monkey kidney cell line used extensively in many virology laboratories, it is striking that viral replication can in fact proceed quite efficiently in the absence of numerous HSV-1 gene products. This class of genes, though dispensable for viral replication in cell culture, is thought to be important for replication in specialized cell types, encode functions that are redundant or overlapping with other viral gene products, or affect pathogenesis in animals. In support of this proposal, HSV-1 genes important for modulating the host immune response, the spread of the virus from peripheral sites of inoculation to the CNS (neuroinvasiveness), and replication within CNS tissues (neurovirulence) have been identified (2); moreover, these genetic determinants of pathogenesis figure prominently in the development of safe, oncolytic HSV-1 strains.

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