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Journal of Virology, February 2003, p. 1927-1939, Vol. 77, No. 3
0022-538X/03/$08.00+0     DOI: 10.1128/JVI.77.3.1927-1939.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

HLA Class II Polymorphisms and Susceptibility to Recurrent Respiratory Papillomatosis

Colin M. Gelder,1* O. Martin Williams,1 Keith W. Hart,1 Siôn Wall,1 Gareth Williams,2 Duncan Ingrams,3 Peter Bull,4 Mike Bunce,5 Ken Welsh,6 Sara E. F. Marshall,7 and Leszek Borysiewicz7

Infection & Immunity, University of Wales College of Medicine,1 University Hospital of Wales, Cardiff,2 Royal Gwent Hospital, Newport,3 Sheffield Children's Hospital, Western Bank, Sheffield,4 Dynal Biotech Ltd., Bromborough, Wirral,5 Clinical Genomics Group, National Heart and Lung Institute,6 Faculty of Medicine, Imperial College, London, United Kingdom7

Received 10 May 2002/ Accepted 1 November 2002

Recurrent respiratory papillomatosis (RRP) is characterised by multiple laryngeal papillomas. Left untreated, the lesions enlarge, spread, and endanger the airway. Medical treatments are unsatisfactory, and repeated surgery remains the mainstay of therapy. RRP is caused by human papillomavirus (HPV) infection. However, since oral HPV infection is common and RRP is rare, other host and/or viral factors may contribute to pathogenesis. In an attempt to identify such factors, we have investigated 60 patients. The patients were HLA class I, II, and tumor necrosis factor TNF typed by sequence-specific primer PCR, and the results compared to those for 554 healthy controls by using Fisher's exact test. Peripheral blood mononuclear cell proliferative responses of 25 controls and 10 patients to HPV-11 L1 virus-like particles (VLP) were compared. Short-term VLP-specific T-cell lines were established, and recognition of L1 was analyzed. Finally, the L1 open reading frames of HPV isolates from four patients were sequenced. Susceptibility to RRP was associated with HLA DRB1*0301 (33 of 60 patients versus 136 of 554 controls, P < 0.0001). The three most severely affected patients were homozygous for this allele. A range of T-cell proliferative responses to HPV-11 VLP were observed in DRB1*0301-positive healthy donors which were comparable to those in DRB1*0301-negative controls. Individuals with juvenile-onset RRP also mounted a range of VLP responses, and their magnitude was negatively correlated with the clinical staging score (P = 0.012 by the Spearman rank correlation). DRB1*0301-positive patients who responded to L1 recognized the same epitope as did matched controls and produced similar cytokines. Sequencing of clinical isolates excluded the possibility that nonresponsiveness was the result of mutation(s) in L1.

* Corresponding author. Mailing address: Infection & Immunity, Tenovus Building, University of Wales College of Medicine, Heath Park, Cardiff CF14 2XX, United Kingdom. Phone: 44-29-2074-2579. Fax: 44-29-2074-3868. E-mail: Viralimmunol{at}cf.ac.uk.

Journal of Virology, February 2003, p. 1927-1939, Vol. 77, No. 3
0022-538X/03/$08.00+0     DOI: 10.1128/JVI.77.3.1927-1939.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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