Abstract
Human papillomaviruses (HPV) have genotype-specific disease associations, with high-risk alpha types causing at least 5% of all human cancers. Despite these conspicuous differences, our data show that high- and low- risk HPV types use similar approaches for genome maintenance and persistence. During the maintenance phase, viral episomes and the host cell genome are replicated synchronously, and for both the high- and low-risk HPV types, the E1 viral helicase is non-essential. During virus genome amplification, replication switches from an E1-independent to an E1-dependent mode, which can uncouple viral DNA replication from that of the host cell. It appears that the viral E2 protein, but not E6 and E7, is required for the synchronous maintenance-replication of both the high and the low-risk HPV types. Interestingly, the ability of the high-risk E6 protein to mediate the proteosomal degradation of p53 and to inhibit keratinocyte differentiation, was also seen with low-risk HPV E6, but in this case was regulated by cell density and the level of viral gene expression. This allows low-risk E6 to support genome amplification, while limiting the extent of E6-mediated cell proliferation during synchronous genome maintenance. Both high and low-risk E7s could facilitate cell cycle re-entry in differentiating cells and support E1-dependent replication. Despite the well-established differences in the viral pathogenesis and cancer risk, it appears that low- and high-risk HPV types use fundamentally similar molecular strategies to maintain their genomes, albeit with important differences in their regulatory control. Our results provide new insights into the regulation of high and low-risk HPV genome replication and persistence in the epithelial basal and parabasal cells layers. Understanding the minimum requirement for viral genome persistence will facilitate the development of therapeutic strategies for clearance.
Highlights
Papillomaviruses (PV) are small double-stranded DNA viruses which infect stratified epithelia, with the completion of their life cycle being intimately linked to the terminal differentiation program of keratinocytes
We carried out a comparative analysis using the most prominent high-risk (HPV16) and lowrisk (HPV11) Human papillomaviruses (HPV) papillomaviruses, focusing on viral genome replication and maintenance in the epithelial basal layer
The characteristic ability of high-risk E6 to degrade p53 and inhibit keratinocyte differentiation was seen with low-risk HPV E6, but in this case was regulated by cell density and the extent of viral gene expression
Summary
Papillomaviruses (PV) are small double-stranded DNA viruses which infect stratified epithelia, with the completion of their life cycle being intimately linked to the terminal differentiation program of keratinocytes. HPVs express a relatively small number of early and late viral genes during their life cycle, which are tightly regulated according to the differentiation stage of the infected keratinocytes. All known papillomaviruses have evolved a group of core genes that were present early during papillomavirus speciation, which share similarities in sequence and protein function. Accessory genes are involved in modifying the cellular environment in order to complete the viral life cycle at the site of infection. Accessory genes play a variety of important functions at different stages of the viral life cycle, such as the maintenance of infection in the basal layer and the amplification of viral genomes in the suprabasal layers. The deregulation of the accessory genes of high-risk HPV can mediate the progression to invasive cancer [4, 14]
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