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Delaying the Expression of Herpes Simplex Virus Type 1 Glycoprotein B (gB) to a True Late Gene Alters Neurovirulence and Inhibits the gB-CD8+ T-Cell Response in the Trigeminal Ganglion

Department of Ophthalmology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15213, USA.
Journal of Virology (Impact Factor: 4.65). 09/2010; 84(17):8811-20. DOI: 10.1128/JVI.00496-10
Source: PubMed

ABSTRACT Following herpes simplex virus type 1 (HSV-1) ocular infection of C57BL/6 mice, activated CD8(+) T cells specific for an immunodominant epitope on HSV-1 glycoprotein B (gB-CD8 cells) establish a stable memory population in HSV-1 latently infected trigeminal ganglia (TG), whereas non-HSV-specific CD8(+) T cells are lost over time. The retention and activation of gB-CD8 cells appear to be influenced by persistent viral antigenic exposure within the latently infected TG. We hypothesized that the low-level expression of gB from its native promoter before viral DNA synthesis is critical for the retention and activation of gB-CD8 cells in the TG during HSV-1 latency and for their ability to block HSV-1 reactivation from latency. To test this, we created a recombinant HSV-1 in which gB is expressed only after viral DNA synthesis from the true late gC promoter (gCp-gB). Despite minor growth differences compared to its rescuant in infected corneas, gCp-gB was significantly growth impaired in the TG and produced a reduced latent genome load. The gCp-gB- and rescuant-infected mice mounted similar gB-CD8 effector responses, but the size and activation phenotypes of the memory gB-CD8 cells were diminished in gCp-gB latently infected TG, suggesting that the stimulation of gB-CD8 cells requires gB expression before viral DNA synthesis. Surprisingly, late gB expression did not compromise the capacity of gB-CD8 cells to inhibit HSV-1 reactivation from latency in ex vivo TG cultures, suggesting that gB-CD8 cells can block HSV-1 reactivation at a very late stage in the viral life cycle. These data have implications for designing better immunogens for vaccines to prevent HSV-1 reactivation.

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    • "gB is a leaky-late gene and, the fact that the reactivating neuron was recognized by a gB-specific CD8 + T cell indicates that IE and early genes are likely to be expressed prior to a CD8 + T cell-mediated block in reactivation . These data indicate that, not only are neurons able to survive high viral genome inputs, they can also survive extensive viral gene expression (Kramer et al., 1998; Ramachandran et al., 2010). This is in agreement with studies using primary neuronal cultures where upon infection with replication defective mutants, transient IE promoter activity was detected in the majority of the neurons in culture prior to the establishment of latent infection (Arthur et al., 2001). "
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