title: 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.
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.
authors.affiliation: Department of Ophthalmology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15213, USA.
authors.forename: Srividya
authors.initials: S
authors.lastname: Ramachandran
authors.forename: Katherine A
authors.initials: KA
authors.lastname: Davoli
authors.forename: Michael B
authors.initials: MB
authors.lastname: Yee
authors.forename: Robert L
authors.initials: RL
authors.lastname: Hendricks
authors.forename: Paul R
authors.initials: PR
authors.lastname: Kinchington
mesh_terms: D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000821:virology; D002522:Chlorocebus aethiops; D005260:Female; D015967:Gene Expression Regulation, Viral; D006561:Herpes Simplex / Q000235:genetics / Q000276:immunology* / Q000821:virology; D018259:Herpesvirus 1, Human / Q000235:genetics / Q000276:immunology / Q000472:pathogenicity*; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D012668:Trigeminal Ganglion / Q000276:immunology* / Q000821:virology; D014709:Vero Cells; D014759:Viral Envelope Proteins / Q000235:genetics* / Q000276:immunology; D014774:Virulence
chemical_list: D014759:Viral Envelope Proteins; C040495:glycoprotein B, Simplexvirus