April 2010
Volume 51, Issue 13
Free
ARVO Annual Meeting Abstract  |   April 2010
Human CD8+ T-Cell Epitopes Protect HLA Transgenic Rabbits from Spontaneous Recurrent Ocular Herpes
Author Affiliations & Notes
  • L. BenMohamed
    The Gavin Herbert Eye Institute, Univ of California-Irvine, Orange, California
  • A. A. Chentoufi
    The Gavin Herbert Eye Institute, Univ of California-Irvine, Orange, California
  • G. Dasgupta
    The Gavin Herbert Eye Institute, Univ of California-Irvine, Orange, California
  • N. D. Christensen
    Hershey Medical Center, Pennsylvania State University, Hershey, Pennsylvania
  • J. Hu
    Hershey Medical Center, Pennsylvania State University, Hershey, Pennsylvania
  • Z. S. Choudhury
    The Gavin Herbert Eye Institute, Univ of California-Irvine, Orange, California
  • A. Azeem
    The Gavin Herbert Eye Institute, Univ of California-Irvine, Orange, California
  • J. V. Jester
    The Gavin Herbert Eye Institute, Univ of California-Irvine, Orange, California
  • S. L. Wechsler
    The Gavin Herbert Eye Institute, Univ of California-Irvine, Orange, California
  • A. B. Nesburn
    The Gavin Herbert Eye Institute, Univ of California-Irvine, Orange, California
  • Footnotes
    Commercial Relationships  L. BenMohamed, None; A.A. Chentoufi, None; G. Dasgupta, None; N.D. Christensen, None; J. Hu, None; Z.S. Choudhury, None; A. Azeem, None; J.V. Jester, None; S.L. Wechsler, None; A.B. Nesburn, None.
  • Footnotes
    Support  NIH grants EY14900, EY15225, and EY16663, Research to Prevent Blindness, The Skirball Program in Molecular Ophthalmology, and The Discovery Eye Foundation.
Investigative Ophthalmology & Visual Science April 2010, Vol.51, 3872. doi:
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      L. BenMohamed, A. A. Chentoufi, G. Dasgupta, N. D. Christensen, J. Hu, Z. S. Choudhury, A. Azeem, J. V. Jester, S. L. Wechsler, A. B. Nesburn; Human CD8+ T-Cell Epitopes Protect HLA Transgenic Rabbits from Spontaneous Recurrent Ocular Herpes. Invest. Ophthalmol. Vis. Sci. 2010;51(13):3872.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose: : Herpes simplex virus 1 (HSV-1) infects the cornea and then establishes latency in sensory neurons of the trigeminal ganglia (TG). Spontaneous reactivation of HSV-1 causes shedding of virus in tears which can result in recurrent Herpes Stromal Keratitis (HSK), a blinding ocular disease. A major gap in our knowledge is: "How to prevent or significantly reduce virus shedding and recurrent HSV eye disease?" HSV-specific CD8+ T-cells appear to decrease in vitro HSV-1 reactivation in explanted mouse TG. Unfortunately, spontaneous reactivation of HSV-1 in mice is extremely rare and recurrent HSK cannot be studied. In contrast, spontaneous reactivation occurs in rabbits and "humanized" HLA transgenic rabbits that mount "human-like" CD8 T-cell immune responses (HLA Tg rabbits) can be used to study protective efficacy of human CD8 T-cell epitopes against spontaneous reactivation and recurrent eye disease.

Methods: : Latently infected HLA Tg rabbits were immunized subcutaneously 3X at 2 week intervals, with lipopeptides bearing HLA-A*0102-restricted gD epitopes. Control rabbits received saline. Ten days after the last immunization, HSV-specific CD8+ T-cell immune responses were analyzed in spleen, conjunctiva, and TG using a CFSE assay. The frequency of HSV peptide-specific CD8+ T-cells was measured using peptide-specific/HLA-A*0102 tetramers. The protective efficacy of asymptomatic CD8 T-cell epitopes against virus shedding in tears was analyzed.

Results: : (1) Immunization induced strong HSV-1 and peptide-specific CD8+ immune responses in spleen, conjunctiva and TG of HLA Tg rabbits. (2) Therapeutic immunization decreased spontaneous reactivation 4-fold (p < 0.0001). (3) Protective immunity correlated with the presence of local Granzyme B+, IFN-gamma+, CD8+ T-cells in TG and draining lymph nodes.

Conclusions: : Therapeutic immunization with human CD8 T-cell gD epitopes can significantly reduce HSV-1 spontaneous recurrent shedding in HLA Tg rabbits. Protection appeared to correlate with induction of CD8 T-cells that produce GrB and IFN-gamma.

Keywords: herpes simplex virus • cornea: basic science • immunomodulation/immunoregulation 
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