ANALYSIS OF THE NUCLEOTIDE-SEQUENCE VARIATION OF THE ANTIGEN-BINDING DOMAIN OF DR-ALPHA AND DQ-ALPHA MOLECULES AS RELATED TO THE EVOLUTION OF PAPILLOMAVIRUS-INDUCED WARTS IN RABBITS

We previously found that regression of skin warts induced by the Shope cottontail rabbit papillomavirus in New Zealand White rabbits, as wel l as malignant conversion of persistent warts, are linked to a restric tion fragment length polymorphism of the major histocompatibility comp lex class II DR alpha and DQ alpha genes. To find out whether this imm unogenetic control could be connected with the antigen binding and pre sentation function of the alpha 1 domain of class II molecules, we hav e sequenced the exon 2 of the four DR alpha EcoRI and six of the seven DQ alpha PvuII restriction fragment length polymorphism alleles ident ified, and deduced the encoded amino acid sequences. We found no amino acid polymorphism among DR alpha alleles, indicating that the alpha 1 domain of the DR alpha chain does not condition wart regression or ca ncer development. In contrast, 27 of the 82 amino acids of the DQ alph a 1 domain were found variable, defining five amino acid sequence alle les. The restriction fragment length polymorphism allele linked to reg ression and another allele not linked to regression share the same alp ha 1 domain, indicating that wart regression is rather conditioned by a closely linked gene. The most divergent DQ alpha 1 allele, however, was that associated with a higher risk of cancer. Alignment of rabbit and human DQ alpha exon 2 alleles disclosed that amino acid charge var iations occur at positions assumed to be important for peptide binding in humans. By modulating the affinity for tumor-specific antigenic pe ptides, such transitions could affect immune surveillance and, thus, c ondition the risk for progression to carcinoma of papillomavirus-assoc iated lesions.