HPV6 VARIANTS FROM MALIGNANT-TUMORS WITH SEQUENCE ALTERATIONS IN THE REGULATORY REGION DO NOT REVEAL DIFFERENCES IN THE ACTIVITIES OF THE ONCOGENE PROMOTERS BUT DO CONTAIN AMINO-ACID EXCHANGES IN THE E6 AND E7PROTEINS

Human papillomavirus type 6 (HPV6) causes benign epithelial proliferat ions of the anogenital and aerodigestive tract, which usually tend to regress spontaneously. The low incidence of HPV6 in carcinomas and the rare progression of the benign tumors has led to the classification o f HPV6 as ''low-risk'' virus. A series of reports, however, described the isolation of HPV6 variants from malignant tumors characterized by sequence rearrangements in the noncoding regulatory region (NCR). It w as speculated that these sequence alterations play a role in tumor pro gression by enhancing the promoter activity and thereby increasing the expression of the viral oncogenes E6 and E7. To elucidate if HPV6 iso lates from malignancies do regularly exhibit sequence alterations in t he regulatory region we first determined and compiled the sequences of the NCRs of a number of isolates from benign and malignant lesions. T his analysis revealed in general a high degree of sequence conservatio n between the individual isolates. Most of the isolates, however, diff ered, independently of origin, by a major and one or two minor inserti ons from the prototype HPV6b sequence. When tested in a functional ass ay these altered NCR sequences did not result in significantly differe nt activities of the promoters responsible for the expression of the E 6 and E7 genes. Further analysis of the E6 and E7 coding region reveal ed a surprisingly high sequence variability within the E6 ORF and allo wed the detection of amino acid exchanges unique for isolates from car cinomas. (C) 1996 Academic Press, Inc.