Differential T helper cell responses to human papillomavirus type 16 E7 related to viral clearance or persistence in patients with cervical neoplasia: a longitudinal study

T D de Gruijl, H J Bontkes, J M Walboomers, M J Stukart, F S Doekhie, A J Remmink, T J Helmerhorst, R H Verheijen, M F Duggan-Keen, P L Stern, C J Meijer, R J Scheper

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T-cell-mediated immune responses against oncogenic human papillomaviruses (HPVs) are believed to play a role in the prevention of cervical carcinogenesis. The in vitro production of interleukin 2 by CD4+ T helper (Th) cells in response to overlapping 20-mer peptides covering the HPV-16 E7 oncoprotein sequence was determined in 72 women with cytological evidence of premalignant cervical intraepithelial neoplasia (CIN) who participated in a nonintervention follow-up (FU) study. In addition, 15 HPV-16 + cervical carcinoma patients were tested. Positive Th cell reactivity was restricted to patients infected by HPV-16 and related types and showed a strong association with viral persistence and disease progression, as evidenced by the high frequency of positive responders among women with persistent HPV-16 infections who ended FU with high-grade CIN III lesions [14 of 15 (93%)]. Women with cervical carcinoma showed responses at a significantly reduced rate [7 of 15 (47%); P = 0.014]. Over the FU period (10-34 months), the level of E7-induced interleukin 2 production from the lymphocytes of CIN patients who had cleared HPV-16 infection showed an inverse correlation with time relative to the last positive HPV DNA test, with 8 of 13 of these patients showing positive responses after clearance. By contrast, among women with persistent HPV-16 infections and developing CIN III lesions (n = 8), there was a rise in Th cell activity over the course of FU. The majority of women responded to an immunogenic region in the carboxyl terminus of the E7 protein (amino acids 67-98). The observed HPV-16 E7-specific Th cell responses may develop as a consequence of increased antigen availability resulting either from clearance or from progression of cervical lesions.

Original languageEnglish
Pages (from-to)1700-6
Number of pages7
JournalCancer research
Issue number8
Publication statusPublished - 15 Apr 1998


  • Adult
  • Carcinoma/genetics
  • Cells, Cultured
  • Cervical Intraepithelial Neoplasia/genetics
  • Female
  • HLA-DQ Antigens/genetics
  • HLA-DR Antigens/genetics
  • Humans
  • Interleukin-2/metabolism
  • Leukocytes, Mononuclear/metabolism
  • Longitudinal Studies
  • Middle Aged
  • Oncogene Proteins, Viral/pharmacology
  • Papillomavirus E7 Proteins
  • Prospective Studies
  • T-Lymphocytes, Helper-Inducer/metabolism
  • Uterine Cervical Neoplasms/genetics

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