title: Circulating herpes simplex type 1 (HSV-1)-specific CD8+ T cells do not access HSV-1 latently infected trigeminal ganglia.
abstract: BACKGROUND
  Therapeutic vaccines can be designed to enhance existing T cell memory populations for increased protection against re-infection. In the case of herpes simplex virus type 1, recurrent disease results from reactivation of latent virus in sensory ganglia, which is controlled in part by a ganglia-resident HSV-specific memory CD8+ T cell population. Thus, an important goal of a therapeutic HSV-1 vaccine would be to enhance this population.
  
  
  METHODS
  HSV-1-infected mice were treated with TAK-779 to block CCR5- and CXCR3-mediated CD8+ T cell migration during both acute and latent infections. Additionally, HSV-1-specific CD8+ T cells were transferred into HSV-1 latently infected mice to mimic the effect of a therapeutic vaccine, and their migration into trigeminal ganglia (TG) was traced during steady-state latency, or during recovery of the TG-resident memory CD8+ T cell population following stress-, and corticosterone-induced depletion and HSV-1 reactivation from latency. Bromodeoxy uridine (BrdU) incorporation measured cell proliferation in vivo.
  
  
  RESULTS
  TAK-779 treatment during acute HSV-1 infection reduced the number of infiltrating CD8+ T cells but did not alter the number of viral genome copies. TAK-779 treatment during HSV latency did not affect the size of the TG-resident memory CD8+ T cell population. Transferred HSV-specific CD8+ T cells failed to access latently infected TG during steady-state latency, or during recovery of the TG resident HSV-specific CD8+ T cell population following exposure of latently infected mice to stress and corticosterone. Recovery of the HSV-specific CD8+ T cell population after stress and corticosterone treatment occurred with homeostatic levels of cell division and did not require CD4+ T cell help.
  
  
  CONCLUSIONS
  Our findings are consistent with the notion that the CD8+ T cells in latently infected TG are a tissue-resident memory (Trm) population that is maintained without replenishment from the periphery, and that when this population is disrupted, it recovers without proliferation or detectable recruitment of HSV-specific CD8+ T cells from the blood. The compartmentalization of the HSV-specific CD8+ memory T cell population in latently infected TG will complicate the design of therapeutic vaccines.
authors.affiliation: Department of Neurology, Klinikum Grosshadern, Ludwig-Maximilians University, Munich, Germany.
authors.forename: Susanne
authors.initials: S
authors.lastname: Himmelein
authors.affiliation: Department of Ophthalmology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213 USA.|Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213 USA.
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: St Leger
authors.affiliation: Department of Ophthalmology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213 USA.
authors.forename: Jared E
authors.initials: JE
authors.lastname: Knickelbein
authors.affiliation: Department of Ophthalmology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213 USA.
authors.forename: Alexander
authors.initials: A
authors.lastname: Rowe
authors.affiliation: Trudeau Institute, Saranac Lake, NY 12983 USA.
authors.forename: Michael L
authors.initials: ML
authors.lastname: Freeman
authors.affiliation: Department of Ophthalmology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213 USA.|Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213 USA.|Department of Molecular Genetics & Biochemistry, University of Pittsburgh, Pittsburgh, PA 15213 USA.
authors.forename: Robert L
authors.initials: RL
authors.lastname: Hendricks