title: 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.
abstract: 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.
authors.affiliation: Department of Pathology, Free University Hospital, Amsterdam, The Netherlands.
authors.forename: T D
authors.initials: TD
authors.lastname: de Gruijl
authors.forename: H J
authors.initials: HJ
authors.lastname: Bontkes
authors.forename: J M
authors.initials: JM
authors.lastname: Walboomers
authors.forename: M J
authors.initials: MJ
authors.lastname: Stukart
authors.forename: F S
authors.initials: FS
authors.lastname: Doekhie
authors.forename: A J
authors.initials: AJ
authors.lastname: Remmink
authors.forename: T J
authors.initials: TJ
authors.lastname: Helmerhorst
authors.forename: R H
authors.initials: RH
authors.lastname: Verheijen
authors.forename: M F
authors.initials: MF
authors.lastname: Duggan-Keen
authors.forename: P L
authors.initials: PL
authors.lastname: Stern
authors.forename: C J
authors.initials: CJ
authors.lastname: Meijer
authors.forename: R J
authors.initials: RJ
authors.lastname: Scheper
mesh_terms: D000328:Adult; D002277:Carcinoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000821:virology; D002478:Cells, Cultured; D005260:Female; D006683:HLA-DQ Antigens / Q000235:genetics; D006684:HLA-DR Antigens / Q000235:genetics; D006801:Humans; D007376:Interleukin-2 / Q000378:metabolism*; D007963:Leukocytes, Mononuclear / Q000378:metabolism; D008137:Longitudinal Studies; D008875:Middle Aged; D009856:Oncogene Proteins, Viral / Q000494:pharmacology*; D050725:Papillomavirus E7 Proteins; D011446:Prospective Studies; D006377:T-Lymphocytes, Helper-Inducer / Q000378:metabolism* / Q000821:virology; D002583:Uterine Cervical Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000821:virology; D002578:Uterine Cervical Dysplasia / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000821:virology
chemical_list: D006683:HLA-DQ Antigens; D006684:HLA-DR Antigens; D007376:Interleukin-2; D009856:Oncogene Proteins, Viral; D050725:Papillomavirus E7 Proteins; C059731:oncogene protein E7, Human papillomavirus type 16