title: Motif analysis of HLA class II molecules that determine the HPV associated risk of cervical carcinogenesis.
abstract: In previous studies, the HLA class II haplotype HLA DRB1*0401-DQB1*0301 was shown to correlate with susceptibility to HPV infection, CIN and cervical cancer while DRB1*0101-DQB1*0501 indicated protection. The present study was designed to identify naturally processed peptide sequences bound to the susceptibility and protective HLA DR-DQ molecules, and use this for T-helper epitope prediction from HPV 16. The HLA class II molecules were obtained by immuno-affinity purification of Epstein-Barr virus B lymphoblastoid cell lines (BCL) homozygous for HLA DQA1*0301-DQB1*0301 and HLA DQA1*0101-DQB1*0501. Peptide pools eluted from the HLA molecules were sequenced by Edman degradation. On the basis of the peptide sequence data obtained, the E6, E7, L1 and L2 proteins of HPV 16 were examined to identify sequences which are likely to bind to HLA DQB1*0301 and DQB1*0501. In addition, motif prediction as well as the binding affinity of predicted peptide motifs for HLA DRB1*0401 and DRB1*0101, the DR alleles associated with susceptibility and protection respectively, was accomplished using published data and a prediction algorithm for the naturally processed peptide sequences bound to these molecules. The HLA DQB1*0501 peptide ligand sequence showed that proline gives an outstanding signal at position 2, Asn/Arg at P1, aliphatic/aromatic amino acids in the central portion, a hydrophobic cluster at P5 with a small contribution by small polar residues and another cluster of aromatic residues towards the C-terminus. The HLA DQB1*0301 sequence also showed that proline gives an outstanding signal at position 2, Thr/Arg at P1, aliphatic/aromatic amino acids in the central portion and an aliphatic cluster with a small contribution by small polar residues at P5. There were no differences in the number of HPV peptides that were predicted as being capable of binding to HLA DQB1*0301 and HLA DQB1*0501, but more HPV peptide motifs were predicted to bind with high affinity to HLA DRB1*0101 than DRB1*0401. The results suggest that HPV 16 peptide epitopes bind with higher affinity to the protective than to susceptible HLA DR-DQ molecules which may lead to a more effective immune response.
authors.affiliation: Department of Gynecological Oncology, Roswell Park Cancer Institute, Buffalo, NY 14263, USA. kunle.odunsi@roswellpark.org
authors.forename: K
authors.initials: K
authors.lastname: Odunsi
authors.forename: T
authors.initials: T
authors.lastname: Ganesan
mesh_terms: D020816:Amino Acid Motifs / Q000235:genetics; D000595:Amino Acid Sequence; D001665:Binding Sites / Q000235:genetics; D002213:Capsid / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D036022:Capsid Proteins; D005260:Female; D006681:HLA-D Antigens / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D006684:HLA-DR Antigens / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D059811:HLA-DRB1 Chains; D006801:Humans; D008969:Molecular Sequence Data; D009856:Oncogene Proteins, Viral / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D027383:Papillomaviridae / Q000235:genetics* / Q000254:growth & development; D050725:Papillomavirus E7 Proteins; D011485:Protein Binding; D012097:Repressor Proteins; D012307:Risk Factors; D020539:Sequence Analysis, Protein; D002583:Uterine Cervical Neoplasms / Q000235:genetics* / Q000821:virology
chemical_list: D036022:Capsid Proteins; C068651:E6 protein, Human papillomavirus type 16; D006681:HLA-D Antigens; D006684:HLA-DR Antigens; D059811:HLA-DRB1 Chains; C553505:HLA-DRB1*04:01 antigen; C063316:L2 protein, Human papillomavirus type 16; D009856:Oncogene Proteins, Viral; D050725:Papillomavirus E7 Proteins; D012097:Repressor Proteins; C059731:oncogene protein E7, Human papillomavirus type 16; C063317:L1 protein, Human papillomavirus type 16