Review
The papillomavirus life cycle

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Abstract

Papillomaviruses infect epithelial cells, and depend on epithelial differentiation for completion of their life cycle. The expression of viral gene products is closely regulated as the infected basal cell migrates towards the epithelial surface. Expression of E6 and E7 in the lower epithelial layers drives cells into S-phase, which creates an environment that is conducive for viral genome replication and cell proliferation. Genome amplification, which is necessary for the production of infectious virions, is prevented until the levels of viral replication proteins rise, and depends on the co-expression of several viral proteins. Virus capsid proteins are expressed in cells that also express E4 as the infected cell enters the upper epithelial layers. The timing of these events varies depending on the infecting papillomavirus, and in the case of the high-risk human papillomaviruses (HPVs), on the severity of neoplasia. Viruses that are evolutionarily related, such as HPV1 and canine oral papillomavirus (COPV), generally organize their productive cycle in a similar way, despite infecting different hosts and epithelial sites. In some instances, such as following HPV16 infection of the cervix or cottontail rabbit papillomavirus (CRPV) infection of domestic rabbits, papillomaviruses can undergo abortive infections in which the productive cycle of the virus is not completed. As with other DNA tumour viruses, such abortive infections can predispose to cancer.

Section snippets

Diversity amongst human papillomaviruses

Papillomaviruses are a diverse group of viruses that have been found in more than 20 different mammalian species, as well as in birds and reptiles. Because of their medical importance, the human papillomaviruses (HPV) have been most extensively studied, and more than 100 different types have now been identified (Bernard, 2005). Although papillomavirus classification is based on nucleotide sequence homology, the differences between evolutionary groups are reflected to some extent, in the

Problems in developing a general model of HPV-associated disease

It is apparent from the above overview that different HPVs have evolved to fill different biological niches, and that in some instances, viruses from different evolutionary groups may be able to target the same epithelial site. Despite this apparent heterogeneity amongst HPVs, they all share certain features that allow them to produce infectious virions following infection. All known HPVs are exclusively epitheliotropic, and unlike certain animal papillomavirus types such as bovine

Organization of the HPV life cycle

Most work on HPVs has centred on the analysis of the high-risk HPV types and in particular on HPV16, which is the primary cause of cervical cancer From these studies and from the analysis of related HPV types (including HPV11 and HPV1), a general pattern of viral gene expression has been worked out (Fig. 1) that can, with modification, be applied to human papillomaviruses from other groups.

Life cycle organization amongst HPVs of different type

Although all papillomaviruses must follow the broad pattern of events described above in order to produce infectious virions, different strategies of productive infection are apparent between the different evolutionary groups. Human papillomaviruses from the B2 supergroup such as HPV4 for instance, do not contain the LXCXE motif necessary for pRB association (Munger et al., 2001) in their E7 protein, suggesting that at a molecular level they may operate differently from viruses of supergroup A,

Regression of lesions and virus latency

Although genome amplification and packaging is necessary for the formation of new virions, infection can have other outcomes. Experimental inoculation of rabbits with ROPV, or the inoculation of dogs with COPV generally leads to the development of lesions that can persist for weeks rather than years (Christensen et al., 2000, Nicholls et al., 2001). Lesions produced by ROPV and COPV resemble in many respects those produced by HPVs, and these viruses have been proposed as models to study mucosal

Productive infection, abortive infection and HPV-associated cancers

In the absence of regression, lesions may persist, and may in some instances progress to cancer. A common characteristic of tumour viruses is their ability to cause tumours at sites where their productive life cycle cannot be completed. This general characteristic appears to hold true for papillomavirus-associated cancers, such as those caused by cottontail rabbit papillomavirus (CRPV) in domestic rabbits, and by BPV1 in horses (Campo, 2002). High-risk HPVs from supergroup A have been

Life cycle organization amongst animal papillomaviruses

The general concepts that relate to the life cycles of human papillomaviruses appear to be applicable to the animal systems that are used to study infection (Peh et al., 2002). In many instances, animal papillomaviruses fall into evolutionary groups that contain no human members suggesting that they have been following an evolutionary path that is distinct from that followed by the HPVs (de Villiers et al., 2004). An exception to this are viruses from the B supergroup, which are widespread in

Acknowledgements

JD is a Programme Leader at the MRC National Institute for Medical Research and is supported by the UK Medical Research Council. Thanks are due to colleagues at NIMR and elsewhere who contributed to the ideas presented in this review.

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