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 (gD53–61, gD70–78, and gD278–286) were joined with a promiscuous human CD4+ T cell peptide epitope (gD49–82) to construct three separate pairs of CD4–CD8 peptides. Each CD4–CD8 peptide pair was then covalently linked to an Nε-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-gD49–82–specific CD4+ T cells in draining lymph node (DLN); induced HLA-restricted HSV-gD53–61, gD70–78, and gD278–286–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.

CXCL10/CXCR3-Dependent Mobilization of Herpes Simplex Virus-Specific CD8 + T EM and CD8 + T RM Cells within Infected Tissues Allows Efficient Protection against Recurrent Herpesvirus Infection and Disease

“…This was confirmed at the functional level by a decrease in the levels of CD107 a/b cytotoxic degranulation and by lower production of both IFN-␥ and tumor necrosis factor alpha (TNF-␣). These results are consistent with our recent finding of a significantly higher level of exhaustion of HSV-1 human epitope-specific CD8 ϩ T cells from TG of HLA Tg rabbits with higher virus reactivation compared to TG of HLA Tg rabbits with less virus reactivation (1,7,74). Because HSV-1 might coopt PD-1, TIM-3, 2B4, VISTA and/or TIGIT immune checkpoints as a strategy to evade CD8 ϩ T cell immune surveillance (70,75), a T cell-based immunotherapy will likely have to be combined with immune checkpoint blockade in order to reverse the dysfunction of antiviral CD8 ϩ T EM and CD8 ϩ T RM cells.…”

Cross-presentation and genome-wide screening reveal candidate T cells antigens for a herpes simplex virus type 1 vaccine

“…This 1,137-amino-acid-long polypeptide is the large subunit of ribonucleotide reductase, is not detected in virions, and is a virulence CD8 responses to HSV-1 proteins gD1 and gB1 were of special interest because they share high sequence homology with HSV-2 proteins that have been used as vaccine candidates (2,(43)(44)(45). HLA-A*0201-restricted CD8 epitopes have been previously reported in both HSV-1 and HSV-2 (16,17). Both proteins were well expressed in the pEXP103 system (Supplemental Figure 2, A and B).…”

“…The virus has a large, 152-kb genome encoding about 77 polypeptides (14,15). BenMohamed et al demonstrated A*0201-restricted responses to HSV-1 glycoprotein D (16,17). A limited number of CD8 epitopes discovered in the context of HSV-2 research are sequence identical and thus cross-reactive with HSV-1.…”

Human Asymptomatic Epitopes Identified from the Herpes Simplex Virus Tegument Protein VP13/14 (UL47) Preferentially Recall Polyfunctional Effector Memory CD44highCD62LlowCD8+TEMCells and Protect Humanized HLA-A*02:01 Transgenic Mice against Ocular Herpesvirus Infection

“…The majority of HSVseropositive individuals are ASYMP (9-12). They do not experience any recurrent herpetic disease, even though the virus spontaneously reactivates from latency and sheds multiple times each year in their tears (13)(14)(15)(16). In contrast, a small proportion of HSV-seropositive individuals are SYMP and experience lifelong recurrences of herpetic disease, usually multiple times a year (17,18), and often require continuous antiviral therapy (i.e., acyclovir and derivatives).…”