A novel HLA (HLA-A*0201) transgenic rabbit model for preclinical evaluation of human CD8+ T cell epitope-based vaccines against ocular herpes.

Abstract

We introduced a novel humanized HLA-A*0201 transgenic (HLA Tg) rabbit model to assess the protective efficacy of a human CD8(+) T cell epitope-based vaccine against primary ocular herpes infection and disease. Each of the three immunodominant human CD8(+) T cell peptide epitopes from HSV-1 glycoprotein D (gD(53-61), gD(70-78), and gD(278-286)) were joined with a promiscuous human CD4(+) T cell peptide epitope (gD(49-82)) to construct three separate pairs of CD4-CD8 peptides. Each CD4-CD8 peptide pair was then covalently linked to an N(epsilon)-palmitoyl-lysine residue via a functional base lysine amino group to construct CD4-CD8 lipopeptides. HLA Tg rabbits were immunized s.c. with a mixture of the three CD4-CD8 HSV-1 gD lipopeptides. The HSV-gD-specific T cell responses induced by the mixture of CD4-CD8 lipopeptide vaccine and the protective efficacy against acute virus replication and ocular disease were determined. Immunization induced HSV-gD(49-82)-specific CD4(+) T cells in draining lymph node (DLN); induced HLA-restricted HSV-gD(53-61), gD(70-78), and gD(278-286)-specific CD8(+) T cells in DLN, conjunctiva, and trigeminal ganglia and reduced HSV-1 replication in tears and corneal eye disease after ocular HSV-1 challenge. In addition, the HSV-1 epitope-specific CD8(+) T cells induced in DLNs, conjunctiva, and the trigeminal ganglia were inversely proportional with corneal disease. The humanized HLA Tg rabbits appeared to be a useful preclinical animal model for investigating the immunogenicity and protective efficacy of human CD8(+) T cell epitope-based prophylactic vaccines against ocular herpes. The relevance of HLA Tg rabbits for future investigation of human CD4-CD8 epitope-based therapeutic vaccines against recurrent HSV-1 is discussed.

• Authors: Aziz A Chentoufi, Gargi Dasgupta, Neil D Christensen, Jiafen Hu, Zareen S Choudhury, Arfan Azeem, James V Jester, Anthony B Nesburn, Steven L Wechsler, Lbachir BenMohamed
• Journal: Journal of immunology (Baltimore, Md. : 1950) (J Immunol) Vol. 184 Issue 5 Pg. 2561-71 (Mar 01 2010) ISSN: 1550-6606 [Electronic] United States
• PMID: 20124097 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Epitopes, T-Lymphocyte
• HLA-A Antigens
• HLA-A*02:01 antigen
• HLA-A2 Antigen
• Herpes Simplex Virus Vaccines
• N(epsilon)-palmitoyllysine
• Peptide Fragments
• Viral Envelope Proteins
• glycoprotein D, Human herpesvirus 1
• Lysine

Topics

• Amino Acid Sequence
• Animals
• Animals, Genetically Modified
• CD4-Positive T-Lymphocytes (immunology, metabolism)
• CD8-Positive T-Lymphocytes (immunology, metabolism)
• Conjunctiva (immunology, metabolism, virology)
• Cornea (immunology, metabolism, virology)
• Epitopes, T-Lymphocyte (chemistry, genetics, immunology)
• HLA-A Antigens (genetics, immunology)
• HLA-A2 Antigen
• Herpes Simplex Virus Vaccines (administration & dosage, genetics, immunology)
• Herpesvirus 1, Human (immunology)
• Humans
• Immunization
• Keratitis, Herpetic (immunology, prevention & control, virology)
• Lymph Nodes (immunology, metabolism, virology)
• Lysine (analogs & derivatives, chemistry)
• Molecular Sequence Data
• Peptide Fragments (chemistry, genetics, immunology)
• Rabbits
• Trigeminal Ganglion (immunology, metabolism, virology)
• Viral Envelope Proteins (chemistry, genetics, immunology)