Evolution of human papillomavirus carcinogenicity

Members of the Alphapapillomavirus genus are the causative agent for virtually all cases of cervical cancer. However, strains (commonly referred to as types) within this genus span the entire range of pathogenicity from highly carcinogenic (e.g., HPV16, odds ratio = 281.9, responsible for 50% of all cervical cancers), moderately carcinogenic (e.g., HPV31) to not carcinogenic (e.g., HPV71). The persistent expression of the viral oncoproteins (E6 and E7) from HPV16 has been shown to be necessary and sufficient to transform primary human keratinocytes in vitro. A plethora of functions have been described for both oncoproteins, and through functional comparisons between HPV16 and HPV6, a subset of these functions have been suggested to be oncogenic. However, extrapolating functional differences from these comparisons is unlikely to tease apart the fine details. In this review, we argue that a thorough understanding of the molecular mechanisms differentiating oncogenic from nononcogenic types should be obtained by performing functional assays in an evolutionary and epidemiological framework. We continue by interpreting some recent results using this paradigm and end by suggesting directions for future inquiries.