An HLA-A2.1-Transgenic Rabbit Model to Study Immunity to Papillomavirus Infection

Abstract

We have established several HLA-A2.1-transgenic rabbit lines to provide a host to study CD8+ T cell responses during virus infections. HLA-A2.1 protein expression was detected on cell surfaces within various organ tissues. Continuous cultured cells from these transgenic rabbits were capable of presenting both endogenous and exogenous HLA-A2.1-restricted epitopes to an HLA-A2.1-restricted epitope-specific CTL clone. A DNA vaccine containing an HLA-A2.1-restricted human papillomavirus type 16 E7 epitope (amino acid residues 82–90) stimulated epitope-specific CTLs in both PBLs and spleen cells of transgenic rabbits. In addition, vaccinated transgenic rabbits were protected against infection with a mutant cottontail rabbit papillomavirus DNA containing an embedded human papillomavirus type 16 E7/82–90 epitope. Complete protection was achieved using a multivalent epitope DNA vaccine based on epitope selection from cottontail rabbit papillomavirus E1 using MHC class I epitope prediction software. HLA-A2.1-transgenic rabbits will be an important preclinical animal model system to study virus-host interactions and to assess specific targets for immunotherapy.

Protective immunity with an E1 multivalent epitope DNA vaccine against cottontail rabbit papillomavirus (CRPV) infection in an HLA-A2.1 transgenic rabbit model

“…Our previous studies have demonstrated that a newly established HLA-A2.1 transgenic rabbit model generated a strong immune response to a well-known HLA-A2.1 restricted epitope from HPV16 E7 in vivo [1]. In this paper, we extend these studies to test the immunogenicity of some naturally existing HLA-A2.1 restricted epitopes in CRPVE1.…”

“…Although E1 is mostly expressed in the upper basal layer of the skin and is not considered as an effective candidate HPV vaccine, several studies have demonstrated that E1 vaccination can either induce regression or provide protection against virus infection in different animal models [7][8][9][10][11][12][13]. We chose five naturally existing HLAA2.1 restricted epitopes from CRPVE1 based on an online MHCI epitope prediction software program to design a multivalent epitope DNA vaccine [1].…”

“…Recently, we established HLA-A2.1 transgenic rabbit lines and demonstrated efficacy for the testing of immunogenicity of a well-known A2-resticted epitope (HPV16E7/82-90) [1]. In the present study, we screened five HLA-A2.1 restricted epitopes from CRPV E1 (selected using online MHCI epitope prediction software) and constructed a multivalent epitope DNA vaccine (CRPVE1ep1-5).…”

Genome-Wide Prediction of Human Papilloma Virus Specific T-Cell Epitopes Using a Combination of Matrix Based Computational Tools

“…HPV 16 peptides E1-LLQQYCLYL254-262 [34], E5-FLLCFCVLL15-23, VLLCVCLLI21-29 [35], E6-KLPQLCTEL18-26 [36,37] and E7-TLHEYMLDL7-15 [38] are known CTL epitopes. E7-LLMGTLGIV82-90 was known to induce the cellular response in HLA A2.1 rabbit model [39] and reduced tumor burden in aged mice [40]. E6-KLPDLCTEL13-22 [41] and E7-TLQDIVLHL [7][8][9][10][11][12][13][14][15] One of the predicted peptides, QLFVTVVDT [42] were proved to be CTL epitopes for HPV 18.…”

Recent advances in strategies for immunotherapy of human papillomavirus‐induced lesions

“…However, studies on viral immunity using rabbit MHC are uninformative in the context of human immune responses. To assess immunity in the context of a human MHC allele, a transgenic rabbit model expressing HLA-A*0201 was generated, 64 which is particularly advantageous because epitopes from HPV proteins can be engineered into similar genes in the CRPV genome, which retains the ability to generate papillomas. This model is very interesting and appropriate to evaluate anti-HPV immune responses after natural infection.…”