The role of a glycoprotein K (gK) CD8+ T-cell epitope of herpes simplex virus on virus replication and pathogenicity.
OBJECTIVE
The authors recently reported that a recombinant HSV-1 expressing two extra copies of glycoprotein K (gK) exacerbated corneal scarring (CS) in mice. The authors also identified a peptide, STVVLITAYGLVLVW, within the signal sequence of gK as an immunodominant gK T-cell-stimulatory region both in vitro and in vivo and identified a highly conserved potential CD8(+) T-cell epitope (ITAYGLVL) within the peptide. In this study, the effect of giving this octamer (8mer) as an eye drop 1 hour before ocular infection with HSV-1 was investigated.


METHODS
Naive mice and rabbits received the gK 8mer or control peptides as eye drops and were then ocularly infected with HSV-1. Virus replication in the eye and trigeminal ganglia (TG), survival, CS, and relative amounts of gB, gK, CD4, CD8, IFN-gamma, and granzyme A/B transcripts were determined in the cornea and TG of infected animals at various times after infection. The effect of the gK 8mer was also analyzed in immunized HLA transgenic mice.


RESULTS
The gK 8mer resulted in a short-term significant increase in virus replication in the eyes of BALB/c mice, C57BL/6 mice, and NZW rabbits. gK 8mer treatment also increased viral neurovirulence and viral induced CS in ocularly infected mice. Moreover, in HSV-infected humanized HLA-A*0201 transgenic mice, the gK 8mer epitope induced strong IFN-gamma-producing cytotoxic CD8(+) T-cell responses, as assessed by CD107a/b expression and IFN-gamma ELISAs.


CONCLUSIONS
gK 8mer induced CD8(+) T-cell responses were unlikely to occur soon enough to account for increased virus replication on day 1 after infection. In contrast, the data are consistent with CD8(+) T cells being involved in the appearance of CS at late times after infection. In addition, the gK peptide may affect viral replication and innate immune responses through other undefined mechanisms.
Mott
Kevin R
KR
Center for Neurobiology and Vaccine Development, Ophthalmology Research, Cedars-Sinai Medical Center Burns and Allen Research Institute, Los Angeles, California 90048, USA.
Chentoufi
Aziz A
AA
Carpenter
Dale
D
BenMohamed
Lbachir
L
Wechsler
Steven L
SL
Ghiasi
Homayon
H
D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D003315:Cornea / Q000821:virology; D003602:Cytotoxicity, Immunologic; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D018984:Epitopes, T-Lymphocyte / Q000276:immunology*; D005260:Female; D018259:Herpesvirus 1, Human / Q000472:pathogenicity* / Q000502:physiology*; D007114:Immunization; D007371:Interferon-gamma; D016849:Keratitis, Herpetic / Q000276:immunology / Q000821:virology*; D051907:Lysosomal Membrane Proteins; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D009883:Ophthalmic Solutions; D010446:Peptide Fragments / Q000008:administration & dosage; D011817:Rabbits; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014764:Viral Proteins / Q000276:immunology*; D014779:Virus Replication / Q000502:physiology*; D052118:Lysosomal-Associated Membrane Protein 1
D018984:Epitopes, T-Lymphocyte; D007371:Interferon-gamma; D051907:Lysosomal Membrane Proteins; D009883:Ophthalmic Solutions; D010446:Peptide Fragments; D014764:Viral Proteins; C052255:Lamp1 protein, mouse; D052118:Lysosomal-Associated Membrane Protein 1; C072448:UL53 protein, Human herpesvirus 1