ReviewThe papillomavirus life cycle
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.
References (76)
- et al.
Association between epidermodysplasia verruciformis-associated human papillomavirus DNA in plucked eyebrow hair and solar keratoses
J Invest Dermatol
(2001) - et al.
Human papillomavirus: a review
Dermatol Clin
(2002) - et al.
Association of the human papillomavirus type 11 E1()E4 protein with cornified cell envelopes derived from infected genital epithelium
Virology
(2000) - et al.
Transmission of human papillomavirus type 11 infection by desquamated cornified cells
Virology
(2001) Animal models of papillomavirus pathogenesis
Virus Res
(2002)- et al.
Rabbit oral papillomavirus complete genome sequence and immunity following genital infection
Virology
(2000) - et al.
Kinetics of in vitro adsorption and entry of papillomavirus virions
Virology
(2004) - et al.
Papillomaviruses infect cells via a clathrin-dependent pathway
Virology
(2003) - et al.
Growth and differentiation of human papillomavirus type 31b positive human cervical cell lines
Gynecol Oncol
(1993) - et al.
Classification of papillomaviruses
Virology
(2004)
Characterisation of events during the late stages of HPV16 infection in vivo using high affinity synthetic fabs to E4
Virology
The L1 major capsid protein of human papillomavirus type 11 recombinant virus-like particles interacts with heparin and cell-surface glycosaminoglycans on human keratinocytes
J Biol Chem
Severe cutaneous papillomavirus disease after haemopoietic stem-cell transplantation in patients with severe combined immune deficiency caused by common gammac cytokine receptor subunit or JAK-3 deficiency
Lancet
Barrier function of the skin: “la raison d’etre” of the epidermis
J Invest Dermatol
Regression of canine oral papillomas is associated with infiltration of CD4+ and CD8+ lymphocytes
Virology
Human papillomavirus type 31b E1 and E2 transcript expression correlates with vegetative viral genome amplification
Virology
The cervical cancer epidemic that screening has prevented in the UK
Lancet
Analysis of the infectious entry pathway of human papillomavirus type 33 pseudovirions
Virology
Inhibition of serum- and calcium-induced differentiation of human keratinocytes by HPV16 E6 oncoprotein: role of p53 inactivation
Virology
Infectious human papillomavirus type 18 pseudovirions
J Mol Biol
New markers for cervical dysplasia to visualise the genomic chaos created by aberrant oncogenic papillomavirus infections
Eur J Cancer
Interaction of the bovine papillomavirus E2 protein with Brd4 tethers the viral DNA to host mitotic chromosomes
Cell
Induction of E6/E7 expression in cottontail rabbit papillomavirus latency following UV activation
Virology
The human papillomavirus type 16 E7 gene product interacts with and trans-activates the AP1 family of transcription factors
EMBO J
Healthy skin of many animal species harbors papillomaviruses, which are closely related to their human counterparts
J Virol
Down-regulation of MHC class I by bovine papillomavirus E5 oncoproteins
Oncogene
Nuclear localization but not PML protein is required for incorporation of the papillomavirus minor capsid protein L2 into virus-like particles
J Virol
The clinical importance of the nomenclature, evolution and taxonomy of human papillomaviruses
J Clin Virol
The causal relation between human papillomavirus and cervical cancer
J Clin Pathol
Immunological events in regressing genital warts
Am J Clin Pathol
Accumulation of RNA homologous to human papillomavirus type 16 open reading frames in genital precancers
J Virol
The papillomavirus minor capsid protein, L2, induces localization of the major capsid protein, L1, and the viral transcription/replication protein, E2, to PML oncogenic domains
J Virol
The E4 proteins and their role in the viral life cycle
Specific interaction between HPV-16 E1-E4 and cytokeratins results in collapse of the epithelial cell intermediate filament network
Nature
Do human papillomaviruses target epidermal stem cells?
Dermatology
Human papillomavirus type 31 E5 protein supports cell cycle progression and activates late viral functions upon epithelial differentiation
J Virol
Assembly and translocation of papillomavirus capsid proteins
J Virol
In vitro synthesis of oncogenic human papillomaviruses requires episomal genomes for differentiation-dependent late gene expression
Proc Natl Acad Sci
Cited by (606)
Cervical cancer: a tale from HPV infection to PARP inhibitors
2023, Genes and DiseasesCitation Excerpt :CIN is a usual health issue among females of reproductive age. Based on their degree of proliferation, CIN can be categorized into three grades, CIN1, CIN2, and CIN3, which are referred to mild, moderate, and severe dysplasia respectively.11 A recent approach based on the Bethesda system for cervical cytology distinguishes CxCa between two categories, low- and high-grade squamous intraepithelial lesions (LSIL and HSIL respectively).
Molecular testing in gynecologic cancer
2023, Diagnostic Molecular Pathology: A Guide to Applied Molecular Testing, Second EditionSmall DNA tumor viruses and human cancer: Preclinical models of virus infection and disease
2022, Tumour Virus Research