Immunologic Control of Mus musculus Papillomavirus Type 1

Persistent papillomas developed in ~10% of out-bred immune-competent SKH-1 mice following MusPV1 challenge of their tail, and in a similar fraction the papillomas were transient, suggesting potential as a model. However, papillomas only occurred in BALB/c or C57BL/6 mice depleted of T cells with anti-CD3 antibody, and they completely regressed within 8 weeks after depletion was stopped. Neither CD4+ nor CD8+ T cell depletion alone in BALB/c or C57BL/6 mice was sufficient to permit visible papilloma formation. However, low levels of MusPV1 were sporadically detected by either genomic DNA-specific PCR analysis of local skin swabs or in situ hybridization of the challenge site with an E6/E7 probe. After switching to CD3+ T cell depletion, papillomas appeared upon 14/15 of mice that had been CD4+ T cell depleted throughout the challenge phase, 1/15 of CD8+ T cell depleted mice, and none in mice without any prior T cell depletion. Both control animals and those depleted with CD8-specific antibody generated MusPV1 L1 capsid-specific antibodies, but not those depleted with CD4-specific antibody prior to T cell depletion with CD3 antibody. Thus, normal BALB/c or C57BL/6 mice eliminate the challenge dose, whereas infection is suppressed but not completely cleared if their CD4 or CD8 T cells are depleted, and recrudescence of MusPV1 is much greater in the former following treatment with CD3 antibody, possibly reflecting their failure to generate capsid antibody. Systemic vaccination of C57BL/6 mice with DNA vectors expressing MusPV1 E6 or E7 fused to calreticulin elicits potent CD8 T cell responses and these immunodominant CD8 T cell epitopes were mapped. Adoptive transfer of a MusPV1 E6-specific CD8+ T cell line controlled established MusPV1 infection and papilloma in RAG1-knockout mice. These findings suggest the potential of immunotherapy for HPV-related disease and the importance of host immunogenetics in the outcome of infection.
Author Summary While most patients clear human papillomavirus (HPV) infection, some develop persistent papillomas, especially if immunocompromised. Likewise, we find a fraction of outbred SKH-1 mice challenged with Mus musculus papillomavirus type 1 (MusPV1/MmuPV1) develop persistent papillomas, whereas most SKH-1 mice, as seen for the inbred C57BL/6 and BALB/c strains, clear the infection. Viral clearance requires both CD4+ and CD8+ T cells, and depletion of either subset permits persistent but subclinical infection. In C57BL/6 mice, CD8+ T cell epitopes were mapped to MusPV1 E6 and E7; however the CD8+ T cell response to E6 dominated and correlated with spontaneous regression. A MusPV1 E6-specific CD8+ T cell line was developed by vaccination and culture in vitro, and its systemic administration once was sufficient to effect papilloma clearance in an immunodeficient mouse. Our observations in inbred and outbred mice challenged with MusPV1 suggest promise for immunotherapy to treat HPV-associated disease.