T-CELL RESPONSE TO COTTONTAIL RABBIT PAPILLOMAVIRUS STRUCTURAL PROTEINS IN INFECTED-RABBITS

Cottontail rabbit papillomavirus (CRPV)-induced papillomas progress at a high frequency to carcinomas and thus can serve as a model for high -cancer-risk human papillomavirus infection. Previously, we have shown that antibodies to nonstructural and structural proteins are detected in only a fraction of papilloma-bearing animals. However, the antibod y response to structural proteins drastically increases as papillomas progress to carcinoma (Y.-L. Lin, L. A. Borenstein, R. Selvakumar, R. Ahmed, and F.O. Wettstein, J. Virol. 67:382-389, 1993). Here we have m onitored the cellular immune response to viral proteins during the cou rse of infection and particularly during progression from papilloma to carcinoma. This was done by measuring the in vitro proliferation resp onse of peripheral blood mononuclear cells (PBMCs) to CRPV structural proteins L1 and L2. The proliferating cells were identified as T cells by selective removal of B or T cells. In general, the T-cell response was low for rabbits at the papilloma stage and none responded to L2. Lymphocytes from animals with carcinomas more frequently and more stro ngly responded to L1, and more than half also responded to L2. In addi tion to stimulation of PBMCs, L1- and L2-specific proliferation could also be demonstrated with lymph node and spleen cells. Overall, our da ta show that progression of papilloma to carcinoma is associated with an increased T-cell response to CRPV structural proteins in addition t o an increased humoral response. This greater immune reactivity, howev er, was not associated with a selectively increased expression of stru ctural proteins, since RNA isolated from papillomas and carcinomas con tained similar relative levels of late and early RNA as shown by dot b lot analysis. Thus, the heightened immune reactivity seen in carcinoma -bearing rabbits most likely reflects greater stimulation of the immun e system owing to dissemination of the tumor. These findings suggest t hat increased immune responses to papillomavirus proteins may be progn ostic of progression to carcinoma and particularly of the development of metastases.