PMID- 24807710
OWN - NLM
STAT- MEDLINE
DCOM- 20140822
LR  - 20211021
IS  - 1098-5514 (Electronic)
IS  - 0022-538X (Print)
IS  - 0022-538X (Linking)
VI  - 88
IP  - 14
DP  - 2014 Jul
TI  - Role of CD8+ T cells and lymphoid dendritic cells in protection from ocular 
      herpes simplex virus 1 challenge in immunized mice.
PG  - 8016-27
LID - 10.1128/JVI.00913-14 [doi]
AB  - The development of immunization strategies to protect against ocular infection 
      with herpes simplex virus 1 (HSV-1) must address the issue of the effects of the 
      strategy on the establishment of latency in the trigeminal ganglia (TG). It is 
      the reactivation of this latent virus that can cause recurrent disease and 
      corneal scarring. CD8(+) T cells and dendritic cells (DCs) have been implicated 
      in the establishment and maintenance of latency through several lines of inquiry. 
      The objective of the current study was to use CD8alpha(-/-) and CD8beta(-/-) mice to 
      further evaluate the contributions of CD8(+) T cells and the CD8alpha(+) and CD8alpha(-) 
      subpopulations of DCs to the protection afforded against ocular infection by 
      immunization against HSV-1 and their potential to increase latency. Neutralizing 
      antibody titers were similar in immunized CD8alpha(-/-), CD8beta(-/-), and wild-type 
      (WT) mice, as was virus replication in the eye. However, on day 3 postinfection 
      (p.i.), the copy number of HSV-1 glycoprotein B (gB) was higher in the corneas 
      and TG of CD8alpha(-/-) mice than those of WT mice, whereas on day 5 p.i. it was 
      lower. As would be anticipated, the lack of CD8alpha(+) or CD8beta(+) cells affected the 
      levels of type I and type II interferon transcripts, but the effects were 
      markedly time dependent and tissue specific. The levels of latent virus in the 
      TG, as estimated by measurement of LAT transcripts and in vitro explant 
      reactivation assays, were lower in the immunized, ocularly challenged CD8alpha(-/-) 
      and WT mice than in their CD8beta(-/-) counterparts. Immunization reduced the 
      expression of PD-1, a marker of T-cell exhaustion, in the TG of ocularly 
      challenged mice, and mock-immunized CD8alpha(-/-) mice had lower levels of PD-1 
      expression and latency than mock-immunized WT or CD8beta(-/-) mice. The expansion of 
      the CD8alpha(-) subpopulation of DCs through injection of WT mice with 
      granulocyte-macrophage colony-stimulating factor (GM-CSF) DNA reduced the amount 
      of latency and PD-1 expression in the TG of infected mice. In contrast, injection 
      of FMS-like tyrosine kinase 3 ligand (Flt3L) DNA, which expanded both 
      subpopulations, was less effective. Our results suggest that the absence of both 
      CD8alpha(+) T cells and CD8alpha(+) DCs does not reduce vaccine efficacy, either directly 
      or indirectly, in challenged mice and that administration of GM-CSF appears to 
      play a beneficial role in reducing latency and T-cell exhaustion. Importance: In 
      the past 2 decades, two large clinical HSV vaccine trials were performed, but 
      both vaccine studies failed to reach their goals. Thus, as an alternative to 
      conventional vaccine studies, we have used a different strategy to manipulate the 
      host immune responses in an effort to induce greater protection against HSV 
      infection. In lieu of the pleiotropic effect of CD8alpha(+) DCs in HSV-1 latency, in 
      this report, we show that the absence of CD8alpha(+) T cells and CD8alpha(+) DCs has no 
      adverse effect on vaccine efficacy. In line with our hypothesis, we found that 
      pushing DC subpopulations from CD8alpha(+) DCs toward CD8alpha(-) DCs by injection of 
      GM-CSF reduced the amount of latent virus and T-cell exhaustion in TG. While 
      these studies point to the lack of a role for CD8alpha(+) T cells in vaccine 
      efficacy, they in turn point to a role for GM-CSF in reducing HSV-1 latency.
CI  - Copyright (c) 2014, American Society for Microbiology. All Rights Reserved.
FAU - Matundan, Harry
AU  - Matundan H
AD  - Center for Neurobiology and Vaccine Development, Ophthalmology Research, 
      Department of Surgery, Los Angeles, California, USA.
FAU - Mott, Kevin R
AU  - Mott KR
AD  - Center for Neurobiology and Vaccine Development, Ophthalmology Research, 
      Department of Surgery, Los Angeles, California, USA.
FAU - Ghiasi, Homayon
AU  - Ghiasi H
AD  - Center for Neurobiology and Vaccine Development, Ophthalmology Research, 
      Department of Surgery, Los Angeles, California, USA ghiasih@cshs.org.
LA  - eng
GR  - R01 EY013615/EY/NEI NIH HHS/United States
GR  - R21 AI093941/AI/NIAID NIH HHS/United States
GR  - AI093941/AI/NIAID NIH HHS/United States
GR  - EY13615/EY/NEI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
DEP - 20140507
PL  - United States
TA  - J Virol
JT  - Journal of virology
JID - 0113724
RN  - 0 (Antibodies, Neutralizing)
RN  - 0 (Antibodies, Viral)
RN  - 0 (Herpesvirus Vaccines)
RN  - 0 (Vaccines, Attenuated)
SB  - IM
MH  - Animals
MH  - Antibodies, Neutralizing/blood
MH  - Antibodies, Viral/blood
MH  - CD8-Positive T-Lymphocytes/*immunology
MH  - Cornea/virology
MH  - Dendritic Cells/*immunology
MH  - Herpesvirus 1, Human/*immunology
MH  - Herpesvirus Vaccines/administration & dosage/*immunology
MH  - Keratitis, Herpetic/immunology/*prevention & control
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Mice, Knockout
MH  - T-Lymphocyte Subsets/*immunology
MH  - Trigeminal Ganglion/virology
MH  - Vaccines, Attenuated/administration & dosage/immunology
PMC - PMC4097799
EDAT- 2014/05/09 06:00
MHDA- 2014/08/26 06:00
PMCR- 2015/01/01
CRDT- 2014/05/09 06:00
PHST- 2014/05/09 06:00 [entrez]
PHST- 2014/05/09 06:00 [pubmed]
PHST- 2014/08/26 06:00 [medline]
PHST- 2015/01/01 00:00 [pmc-release]
AID - JVI.00913-14 [pii]
AID - 00913-14 [pii]
AID - 10.1128/JVI.00913-14 [doi]
PST - ppublish
SO  - J Virol. 2014 Jul;88(14):8016-27. doi: 10.1128/JVI.00913-14. Epub 2014 May 7.