Elsevier

Vaccine

Volume 30, Supplement 5, 20 November 2012, Pages F55-F70
Vaccine

Review
The Biology and Life-Cycle of Human Papillomaviruses

https://doi.org/10.1016/j.vaccine.2012.06.083Get rights and content

Abstract

Human papillomaviruses (HPVs) comprise a diverse group, and have different epithelial tropisms and life-cycle strategies. Many HPVs are classified as low-risk, as they are only very rarely associated with neoplasia or cancer in the general population. These HPVs typically cause inapparent/inconspicuous infections, or benign papillomas, which can persist for months or years, but which are eventually resolved by the host's immune system. Low-risk HPVs are difficult to manage in immunosuppressed people and in individuals with genetic predispositions, and can give rise to papillomatosis, and in rare instances, to cancer. The high-risk HPV types are, by contrast, a cause of several important human cancers, including almost all cases of cervical cancer, a large proportion of other anogenital cancers and a growing number of head and neck tumours. The high-risk HPV types constitute a subset of the genus Alphapapillomavirus that are prevalent in the general population, and in most individuals cause only inconspicuous oral and genital lesions. Cancer progression is associated with persistent high-risk HPV infection and with deregulated viral gene expression, which leads to excessive cell proliferation, deficient DNA repair, and the accumulation of genetic damage in the infected cell. Although their life-cycle organisation is broadly similar to that of the low-risk HPV types, the two groups differ significantly in their capacity to drive cell cycle entry and cell proliferation in the basal/parabasal cell layers. This is thought to be linked, at least in part, to different abilities of the high- and low-risk E6 proteins to modulate the activity of p53 and PDZ-domain proteins, and the differential ability of the E7 proteins to target the several different members of the retinoblastoma protein family.

This article forms part of a special supplement entitled “Comprehensive Control of HPV Infections and Related Diseases” Vaccine Volume 30, Supplement 5, 2012.

Section snippets

The diversity of human papillomaviruses and the diseases that they cause

To date, more than 150 human papillomavirus (HPV) types have been completely sequenced (Fig. 1), along with over 60 animal papillomaviruses (PV) (see Papillomavirus Episteme (PaVE); http://pave.niaid.nih.gov/#home) and [1]). The presence of PVs in mammals, as well as in various diverse hosts, including birds, turtles and snakes, suggests that they may be ubiquitously present amongst present day amniotes (i.e., mammals, birds and reptiles) [2].

Papillomavirus types found in humans are divided

High- and low-risk types and their association with cancers

The Alpha PVs are divided into cutaneous and mucosal types, and the mucosal types are further subdivided into high-risk and low-risk groups [1]. The cutaneous Alpha types are also ‘low-risk’, and include HPV2 and 57, which cause common warts, and HPV3 and 10, which cause flat warts [1], [20].

The low-risk mucosal types (Fig. 2A), which despite their name can also cause cutaneous genital lesions, share a low-risk HPV life-cycle organisation and do not typically cause neoplasia [29] (Figs. 4B and 5

The normal productive life-cycle of high- and low-risk papillomaviruses

Whether a productive life-cycle is or is not completed depends on the nature of the epithelial site where infection occurs, as well as on the presence of external factors such as hormones [58] and cytokines [59]. Experimental models suggest that infection requires access of virus particles (composed of viral DNA and two capsid proteins, L1 and L2, which form icosahedral capsid [60], [61]) to the basal lamina, and the interaction with heparin sulphate proteoglycans [62], [63], [64] and possibly

Life-cycle deregulation and cancer progression

The ordered expression of viral gene products that leads to virus particle production is disrupted in HPV-associated neoplasia (Figure 6, Figure 7). In cervical disease, where most research has been done, it is generally thought that the levels of E6 and E7 expression increase from cervical intraepithelial neoplasia grade 1 to 3 (CIN1 to CIN3), and that these changes in gene expression directly underlie the neoplastic phenotype. In this scheme, CIN1 lesions typically retain the ability to

Lesion regression, latency and clearance

Although high-risk HPV infection is common, with over 80% of women becoming infected at some stage in their life, cervical cancer arises only rarely as a result of infection. Most infections are cleared as a result of a cell-mediated immune response, and do not persist long enough for deregulated gene expression and the accumulation of secondary genetic errors to occur. HPV16 has an average length of persistence that is longer than most other high-risk types, and this may contribute to its

Conclusions

Human papillomaviruses have evolved over millions of years to survive in a wide range of animal species, including humans. As is typical of viruses that have co-evolved with their hosts, many PVs produce only chronic, inapparent infections, and produce virions from the surface of infected epithelium without apparent detriment to the host. This is the case for many Beta and Gamma HPV types. However, not all HPV types use the same strategy, and it appears that several of the Alpha PVs, in

Acknowledgements

The E4/MCM staining shown in Fig. 7A was produced by Heather Griffin (NIMR, London, UK) using a tissue section prepared as part of an ongoing collaboration with Robert Jach, Krzysztof Okoń and Grzegorz Dyduch at the Jagiellonian University Medical College, Krakow, Poland. The LCM images shown in Fig. 7B was produced by Rene Bax and David Jenkins at DDL, Voorburg, Holland. IG Bravo is partially supported by public grants from the disappeared Spanish Ministry for Science and Innovation

References (230)

  • K.Y. Chow et al.

    A pivotal role for CXCL12 signaling in HPV-mediated transformation of keratinocytes: clues to understanding HPV-pathogenesis in WHIM syndrome

    Cell Host Microbe

    (2010)
  • V. Bouvard et al.

    El Ghissassi F, et al., A review of human carcinogens--Part B: biological agents

    The lancet oncology

    (2009)
  • M. Schiffman et al.

    The carcinogenicity of human papillomavirus types reflects viral evolution

    Virology

    (2005)
  • M. Schiffman et al.

    Human papillomavirus and cervical cancer

    Lancet

    (2007)
  • L. Barrow-Laing et al.

    Low- and high-risk human papillomavirus E7 proteins regulate p130 differently

    Virology

    (2010)
  • T. Yu et al.

    The role of viral integration in the development of cervical cancer

    Cancer Genet Cytogenet

    (2005)
  • P. Gariglio et al.

    The role of retinoid deficiency and estrogens as cofactors in cervical cancer

    Arch Med Res

    (2009)
  • A.L. Combita et al.

    Gene transfer using human papillomavirus pseudovirions varies according to virus genotype and requires cell surface heparan sulfate

    FEMS Microbiol Lett

    (2001)
  • J.T. Schiller et al.

    Current understanding of the mechanism of HPV infection

    Gynecol Oncol

    (2010)
  • N.A. McMillan et al.

    Expression of the alpha6 integrin confers papillomavirus binding upon receptor-negative B-cells

    Virology

    (1999)
  • P.M. Day et al.

    Papillomaviruses infect cells via a clathrin-dependent pathway

    Virology

    (2003)
  • V. Bouvard et al.

    Carcinogenicity of malaria and of some polyomaviruses

    Lancet Oncol

    (2012)
  • J.L. Parish et al.

    ChlR1 is required for loading papillomavirus E2 onto mitotic chromosomes and viral genome maintenance

    Mol Cell

    (2006)
  • A.A. McBride

    Replication and partitioning of papillomavirus genomes

    Adv Vir Res

    (2008)
  • G.A. Maglennon et al.

    Persistence of viral DNA in the epithelial basal layer suggests a model for papillomavirus latency following immune regression

    Virology

    (2011)
  • K. Kim et al.

    E1 protein of bovine papillomavirus 1 is not required for the maintenance of viral plasmid DNA replication

    Virology

    (2002)
  • J. Doorbar

    Molecular biology of human papillomavirus infection and cervical cancer

    Clin Sci (Lond)

    (2006)
  • J. Ekström et al.

    High throughput sequencing reveals diversity of Human Papillomaviruses in cutaneous lesions

    Int J Cancer

    (2011)
  • I. Nindl et al.

    Human papillomaviruses and non-melanoma skin cancer: basic virology and clinical manifestations

    Dis Markers

    (2007)
  • Bottalico D, Chen Z, Dunne A, Ostoloza J, McKinney S, Sun C, et al. The oral cavity contains abundant known and novel...
  • O. Forslund

    Genetic diversity of cutaneous human papillomaviruses

    J Gen Virol

    (2007)
  • M. Woolhouse et al.

    Ecological origins of novel human pathogens

    Crit Rev Microbiol

    (2007)
  • M. Gottschling et al.

    Multiple evolutionary mechanisms drive papillomavirus diversification

    Mol Biol Evol

    (2007)
  • S.D. Shah et al.

    Analysis of host-parasite incongruence in papillomavirus evolution using importance sampling

    Mol Biol Evol

    (2010)
  • M. Gottschling et al.

    Quantifying the phylodynamic forces driving papillomavirus evolution

    Mol Biol Evol

    (2011 Jul)
  • C.J. Lacey et al.

    Chapter 4: Burden and management of non-cancerous HPV-related conditions: HPV-6/11 disease

    Vaccine

    (2006)
  • T. Major et al.

    The characteristics of human papillomavirus DNA in head and neck cancers and papillomas

    J Clin Pathol

    (2005)
  • A.J. Donne et al.

    Recurrent respiratory papillomatosis: an uncommon but potentially devastating effect of human papillomavirus in children

    Int J STD AIDS

    (2010)
  • P.R. Hsueh

    Human papillomavirus, genital warts, and vaccines

    J Microbiol Immunol Infect

    (2009)
  • C.S. Derkay

    Task force on recurrent respiratory papillomas. A preliminary report

    Arch Otolaryngol Head Neck Surg

    (1995)
  • Z. Chen et al.

    Evolution and taxonomic classification of human papillomavirus 16 (HPV16)-related variant genomes: HPV31, HPV33, HPV35, HPV52, HPV58 and HPV67

    PLoS One

    (2011)
  • A. Wikstrom et al.

    Penile intraepithelial neoplasia: histopathological evaluation, HPV typing, clinical presentation and treatment

    J Eur Acad Dermatol Venereol.

    (2012 Mar)
  • R.J. Silva et al.

    Persistence and clearance of HPV from the penis of men infected and non-infected with HIV

    J Med Virol

    (2011)
  • Z. Szentirmay et al.

    Human papillomavirus in head and neck cancer: molecular biology and clinicopathological correlations

    Cancer Metastasis Rev

    (2005)
  • S. Syrjänen et al.

    Human papillomaviruses in oral carcinoma and oral potentially malignant disorders: a systematic review

    Oral Dis

    (2011)
  • K. Middleton et al.

    Organization of human papillomavirus productive cycle during neoplastic progression provides a basis for selection of diagnostic markers

    J Virol

    (2003)
  • A. Gewirtzman et al.

    Epidermodysplasia verruciformis and human papilloma virus

    Curr Opin Infect Dis

    (2008)
  • Lebwohl MG, Rosen T, Stockfleth E. The role of human papillomavirus in common skin conditions: current viewpoints and...
  • M. Dubina et al.

    Viral-associated nonmelanoma skin cancers: a review

    Am J Dermatopathol

    (2009)
  • S. Weissenborn et al.

    Beta-papillomavirus DNA loads in hair follicles of immunocompetent people and organ transplant recipients

    Med Microbiol Immunol

    (2012 May)
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