title: HPV 16 infection and progression of cervical intra-epithelial neoplasia: analysis of HLA polymorphism and HPV 16 E6 sequence variants.
abstract: High-risk human papillomavirus (HPV) infection plays an important role in cervical intra-epithelial neoplasia (CIN), but HPV infection alone is not sufficient for progression to cervical cancer. Several lines of evidence suggest that cellular immune surveillance is important in the control of HPV infection and the development of CIN. The presentation to T cells of target viral peptides in the context of HLA molecules is influenced by the genetic polymorphisms of both HPV and HLA and thereby influences the host immune response and clinical outcome of HPV infection. HLA class I and II polymorphism in susceptibility for HPV 16 infection, development and progression of CIN was analyzed in a group of 118 patients participating in a prospective study of women with initial abnormal cytology. Patients were stratified according to HPV status and course of the disease. HLA-B*44 frequency was increased in the small group of patients with a lesion that showed clinical progression during follow-up [OR = 9.0 (4.6-17.5), p = 0.007]. HLA-DRB1*07 frequency was increased among HPV 16-positive patients compared with patients who were negative for all HPV types [OR = 5.9 (3.0-11.3), p = 0.02]. Our results are consistent with the immunogenetic factors associated with disease progression being different from those associated with susceptibility to HPV 16 infection. Sequencing of the HPV 16 E6 and E7 open reading frames of a subset of these patients (n = 40) showed the frequency of HPV 16 variants to be similar to other studies. However, there was no significant correlation between variant incidence and disease progression or viral persistence and no significant correlation with any HLA allele. It appears that multiple HLA types can influence HPV 16-associated cervical dysplasia but the role of HPV 16 variants in disease progression and susceptibility in relation to HLA polymorphism remains unclear.
authors.affiliation: Department of Pathology, Free University Hospital, Amsterdam, The Netherlands.
authors.forename: H J
authors.initials: HJ
authors.lastname: Bontkes
authors.forename: M
authors.initials: M
authors.lastname: van Duin
authors.forename: T D
authors.initials: TD
authors.lastname: de Gruijl
authors.forename: M F
authors.initials: MF
authors.lastname: Duggan-Keen
authors.forename: J M
authors.initials: JM
authors.lastname: Walboomers
authors.forename: M J
authors.initials: MJ
authors.lastname: Stukart
authors.forename: R H
authors.initials: RH
authors.lastname: Verheijen
authors.forename: T J
authors.initials: TJ
authors.lastname: Helmerhorst
authors.forename: C J
authors.initials: CJ
authors.lastname: Meijer
authors.forename: R J
authors.initials: RJ
authors.lastname: Scheper
authors.forename: F R
authors.initials: FR
authors.lastname: Stevens
authors.forename: P A
authors.initials: PA
authors.lastname: Dyer
authors.forename: P
authors.initials: P
authors.lastname: Sinnott
authors.forename: P L
authors.initials: PL
authors.lastname: Stern
mesh_terms: D000328:Adult; D000483:Alleles; D018450:Disease Progression; D005260:Female; D014644:Genetic Variation; D005838:Genotype; D015395:Histocompatibility Antigens Class I / Q000235:genetics*; D000949:Histocompatibility Antigens Class II / Q000235:genetics*; D006801:Humans; D008875:Middle Aged; D009856:Oncogene Proteins, Viral / Q000235:genetics*; D016366:Open Reading Frames; D027383:Papillomaviridae / Q000235:genetics*; D050725:Papillomavirus E7 Proteins; D030361:Papillomavirus Infections / Q000150:complications* / Q000235:genetics / Q000821:virology; D011110:Polymorphism, Genetic; D011446:Prospective Studies; D012097:Repressor Proteins; D014412:Tumor Virus Infections / Q000150:complications* / Q000235:genetics / Q000821:virology; D002583:Uterine Cervical Neoplasms / Q000473:pathology / Q000821:virology*; D002578:Uterine Cervical Dysplasia / Q000473:pathology / Q000821:virology*
chemical_list: C068651:E6 protein, Human papillomavirus type 16; D015395:Histocompatibility Antigens Class I; D000949:Histocompatibility Antigens Class II; D009856:Oncogene Proteins, Viral; D050725:Papillomavirus E7 Proteins; D012097:Repressor Proteins; C059731:oncogene protein E7, Human papillomavirus type 16