Sequence analysis of the long control region of human papillomavirus type 16 variants and functional consequences for P97 promoter activity

Genital human papillomaviruses (HPV) are considered to be one of the main r isk factors for the development of cervical cancer. The P97 promoter at the E6-proximal end of the long control region (LCR) regulates the transcripti on of viral genes, especially the oncogenes E6 and E7. The LCR contains bin ding sites of several viral and cellular transcription factors, which eithe r activate or repress the P97 promoter. Intratype variants of HPV-16 belong to six geographically clustered phylogenetic groups distributed all over t he world. These variants exhibit differences in E6 protein activities and i n tumour progression in vivo. Seven HPV-16 variants were investigated by se quencing the entire LCR (nt 7060-124) and by comparing the transcriptional activities of their P97 promoters. Previously unknown nucleotide variations were identified in all LCRs investigated. In luciferase assays, 3.3- and 2 .8-fold increases in P97 promoter activity were detected in the Asian Ameri can c and North American 1 variants when compared with the European referen ce clone. The African variants 1a and 2a exhibited P97 promoter activities comparable to the European reference clone. After recombining different LCR fragments, the region responsible for enhanced transcription in the Asian American c and North American 1 variants could be attributed to the E6-prox imal end of the LCR (nt 7619-124).