T-Cell Response to Human Papillomavirus Type 58 L1, E6, and E7 Peptides in Women with Cleared Infection, Cervical Intraepithelial Neoplasia, or Invasive Cancer

Paul K S Chan,Shih-Jen Liu,S M Ngai,Pele Chong,Stephen Man,Jo L K Cheung,Winnie Yeo,T H Cheung

doi:10.1128/cvi.00105-10

Abstract

Human papillomavirus type 58 (HPV-58) exists in a relatively high prevalence in certain parts of the world, including East Asia. This study examined the T-cell response to HPV-58 L1, E6, and E7 peptides among women with cleared infection, cervical intraepithelial neoplasia grade 2 (CIN2) or CIN3, or invasive cervical cancer (ICC). Peptides found to be reactive in the in vitro peptide binding assay or mouse-stimulating study were tested with a gamma interferon (IFN-gamma) enzyme-linked immunospot (ELISPOT) assay to detect peptide-specific responses from the peripheral blood mononuclear cells (PBMC) collected from 91 HPV-58-infected women (32 with cleared infection, 16 CIN2, 15 CIN3, and 28 ICC). Four HLA-A11-restricted HPV-58 L1 peptides, located at amino acid positions 296 to 304, 327 to 335, 101 to 109, and 469 to 477, showed positive IFN-gamma ELISPOT results and were mainly from women with cleared infection. Two HLA-A11-restricted E6 peptides (amino acid positions 64 to 72 and 94 to 102) and three HLA-A11-restricted E7 peptides (amino acid positions 78 to 86, 74 to 82, and 88 to 96) showed a positive response. A response to E6 and E7 peptides was mainly observed from subjects with CIN2 or above. One HLA-A2-restricted E6 peptide, located at amino acid position 99 to 107, elicited a positive response in two CIN2 subjects. One HLA-A24-restricted L1 peptide, located at amino acid position 468 to 476, also elicited a positive response in two CIN2 subjects. In summary, this study has identified a few immunogenic epitopes for HPV-58 E6 and E7 proteins. It is worthwhile to further investigate whether responses to these epitopes have a role in clearing an established cervical lesion.

Highlights

Infection with high-risk human papillomaviruses (HPV) is a necessary cause for cervical cancer [14, 21, 33]
Two vaccines have been approved for clinical use to prevent HPV infection and its potential consequences of developing cervical intraepithelial neoplasia (CIN) and invasive cervical cancer (ICC) [27]
In the mouse immunization study, five A24restricted L1 peptides, two A24-restricted E6 peptides, three A2-restricted E6 peptides, and one A2-restricted E7 peptide showed positive results (Tables 2 and 3). These peptides were selected for further IFN-␥ enzyme-linked immunospot (ELISPOT) study using human peripheral blood mononuclear cells (PBMC) samples

Summary

Introduction

Infection with high-risk human papillomaviruses (HPV) is a necessary cause for cervical cancer [14, 21, 33]. Two vaccines have been approved for clinical use to prevent HPV infection and its potential consequences of developing cervical intraepithelial neoplasia (CIN) and invasive cervical cancer (ICC) [27]. Both vaccines are prophylactic and contain HPV-16 and HPV-18 L1 protein-based virus-like particles. Human cytotoxic T-lymphocytes against HPV-positive cervical cell lines [1, 13, 25] These findings have led to the search for peptides that can elicit or augment an HPV-specific cytotoxic cellular response from patients who have developed preinvasive or invasive cervical neoplasia [4, 29, 35]. Data on T-cell response to HPV-58 peptides are not available; the aim of this study was to characterize the T-cell response against peptides derived from the L1, E6, and E7 proteins of HPV-58 among women with cleared infection or cervical neoplasia

Objectives

Methods

Results