high-risk human papillomaviruses (hpvs), such as hpv16, are implicated in causing virtually all cases of cervical cancer. molecular therapies capable of targeting hpv16 e6 oncoprotein expression can selectively eliminate infected cells without the unwanted side effects in healthy cells seen with traditional treatments. an efficient approach is the use of synthetic small interfering rna (sirna) to target and degrade e6 mrna. two common variants of the hpv16 e6 gene, european prototype (ep e6) and asian-american (aa e6), differ due to six single nucleotide polymorphisms (snps) and aa e6 has been shown to have a greater oncogenic potential than ep e6. in silico modeling was used to demonstrate that these aa e6 snps cause its mrna to have a less compacted structure than that of ep e6. however, transfection of an e6 sirna containing no base pair mismatches with either variant demonstrated that these structural changes did not result in aa e6 having a significantly different amount of e6 knockdown than ep e6, as determined using rt-qpcr. interestingly, equivalent knockdown of e6 mrna in both variants yielded differing responses in the restoration of downstream cellular process abrogated by e6. htert mrna levels were equally restored to those of phfks in aa e6. there was a greater elevation of ifn b mrna expression in ep compared to aa e6. aa e6 ifn k mrna and p53 protein levels were elevated more following treatment with a lower dose of e6 sirna than those of ep e6. these data add to the growing body of evidence that the aa e6 protein may have unique properties or disrupt cellular processes through different mechanisms compared to ep e6. these findings also have translational implications (e.g. different doses of e6 sirna may be required to achieve the same therapeutic effect, depending on the variant involved).