VARIATION OF HUMAN PAPILLOMAVIRUS TYPE-6 (HPV-6) AND HPV-11 GENOMES SAMPLED THROUGHOUT THE WORLD

We examined the genomic diversity of human papillomavirus type 6 (HPV- 6) and HPV-11 isolates from different parts of the world by comparing the nucleotide sequences of part of the long control region of three r eference clones and 62 HPV-6 and 40 HPV-11 isolates from Africa, Europ e, Asia, and North and South America. The genomic sequence of the HPV- 6b reference type had to be amended by inclusion of a 94-bp segment, w hich is also present with minor differences in HPV-6a. Aside from two small inserts typical of all variants related to HPV-6a and three inse rts found in HPV-11 variants, no major alterations to the size of the long control regions of these viruses were observed. This corrects the previous impression that these two HPV types are highly polymorphic. Altogether, 19 HPV-6 and 10 HPV-11 variant genomes could be distinguis hed, and most of the differences were due to point substitutions. The variants of either type were continuously connected in phylogenetic tr ees rather than clustered separately into subtype groups. Thirteen mut ations, namely, the two HPV-6a inserts and 11 substitutions in HPV-6 o r HPV-11 variants, reduced the dissimilarity between the types, but th ey bridged only a small fraction of the genetic distance between the t wo types. Genomes more obviously intermediate between HPV-6 and HPV-11 were not found and probably do not exist any more. A single HPV-11 va riant was found in Africa, but otherwise, no significant correlations of HPV-6 or HPV-11 variants with geography or ethnicity of the patient cohort were found. Functional analysis of diverse enhancer variants s howed activities that differed two- to threefold, and it must be consi dered that transcriptional differences may alter the biology or pathol ogy of these viruses. Similar variants were found in lesions from anat omically different sites and in both benign and malignant lesions.