Ubiquitin-Fused and/or Multiple Early Genes from Cottontail Rabbit Papillomavirus as DNA Vaccines

摘要: Cervical human papillomavirus (HPV) infection is an extremely common sexually transmitted disease that affects estimated 15% of women in the United States (18). Persistent lesions can be treated, but available treatments do not necessarily prevent recurrence (from latently infected tissues) and reinfection (with same or other HPV types). carcinogenesis initiated by with high-risk types (3, 28, 39), most which are type 16 (HPV-16) HPV-18. Worldwide, cervical cancer second third (23). Vaccination against to treat premalignant could substantially decrease morbidity mortality from cancer. The ideal vaccine would only primary forming also provide therapy for established lesions. While humoral antibodies infection, cellular immune responses early (intracellular) proteins mediate both functions, providing helper cell activities necessary proliferation differentiation B cells and/or into cytotoxic T (CTLs) as well elaborating inhibitory cytokines, thereby participating occur during preclinical stage those after establishment lesions. The small-animal model long-term persistence malignant progression cottontail rabbit (CRPV)-domestic (4). We previously reported a DNA encoding CRPV protein E6 induced significant protection challenge (34). vaccine's efficacy was dramatically improved priming sites vaccination granulocyte-macrophage colony-stimulating factor (GM-CSF), cytokine stimulates local recruitment maturation professional antigen-presenting (20), initiate vaccine-induced (6, 19). Another strategy enhancing increase efficiency antigen processing—for example, using gene encodes ubiquitin-fused version target (13). Ubiquitinated enter proteasomal pathway, where they processed presented through major histocompatibility complex (MHC) class I pathway stimulate clonal expansion MHC I-restricted, typically CD8+, (16, 29, 42). Rodriguez et al. showed fusion ubiquitin monomer nucleoprotein lymphocytic choriomeningitis virus led more rapid complete degradation (25). When incorporated prophylactic mice, reduced viral titer severity virus-induced disease. Similar ubiquitin-based strategies pathogens have been effective (22, 36, 37). A different approach generating broad vaccinate multiple (2), increasing chances inducing population-wide immunity individuals, whose epitopes within given may differ widely. genes likely useful prevention treatment low-grade E1, E2, E6, E7. Each these performs critical functions life cycle (30, 38), expressed virtually all (7, 31), required papilloma formation (5, 21, 41). Another potential advantage targeting proteins, particularly E1 contain highly conserved regions (1), so one might cross-react types. Vaccines E7 oncoproteins additionally used high-grade 31). The first goal present study determine whether protect rabbits following this superior GM-CSF priming. vaccines were capable any combinations help hinder development protective immunity. Finally, we combined tested combination versions proteins.