Tumourigenesis Driven by the Human Papillomavirus Type 16 Asian-American E6 Variant in a Three-Dimensional Keratinocyte Model

摘要: Infection with a transforming human papillomavirus (HPV) such as type 16 (of species Alphapapillomavirus 9) causes ano-genital and oral tumours via viral persistence in squamous cell epithelia. Epidemiological studies showed that the naturally occurring HPV16 Asian-American (AA) variant (sublineage D2/D3) is found more often than European Prototype (EP) A1) high-grade cervical neoplasia compared to non-cancer controls. Just three amino acid changes within early gene, E6, of AA have been linked this augmented tumourigenicity. The AAE6 variant's greater immortalizing potential over EPE6 has recently confirmed retrovirally-transduced keratinocytes expressing E6 gene only. However, tumourigenic role full-length genome not yet addressed regard these variants. To investigate process context two genotypes, an organotypic tissue culture model was used simulate HPV infectious life cycle. demonstrated enhanced ability drive cycle toward tumourigenesis, evidenced phenotypically—by severe grade epithelial dysplasia higher proliferation deregulated differentiation, molecularly—by high oncogene E7 expression, but lack productive markers. In contrast, had low E1∧E4 indicative We suggest increased integration into host for one possible mechanism observed differences from EPE6. Additionally, we downstream effects on immortalization innate immune evasion. This study highlights how minor genomic variations viruses can significant affect their ability.