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 well as malignant conversion of persistent warts, are linked to a restriction fragment length polymorphism of the major histocompatibility complex class II DR alpha and DQ alpha genes. To find out whether this immunogenetic control could be connected with the antigen binding and presentation function of the alpha 1 domain of class II molecules, we have sequenced the exon 2 of the four DR alpha EcoRI and six of the seven DQ alpha PvuII restriction fragment length polymorphism alleles identified, 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 cancer development. In contrast, 27 of the 82 amino acids of the DQ alpha 1 domain were found variable, defining five amino acid sequence alleles. The restriction fragment length polymorphism allele linked to regression and another allele not linked to regression share the same alpha 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 variations occur at positions assumed to be important for peptide binding in humans. By modulating the affinity for tumor-specific antigenic peptides, such transitions could affect immune surveillance and, thus, condition the risk for progression to carcinoma of papillomavirus-associated lesions.