Papillomaviruses are a large family of small deoxyribonucleic acid (DNA) tumour viruses that cause hyperproliferative warts of cutaneous and mucosal epithelium. These viruses are ubiquitous in the animal kingdom and infect reptiles, birds and mammals and probably originated 350 million years ago. Subsets of human papillomaviruses (HPVs), referred to as ‘high‐risk’ types are associated with anogenital cancers (uterine cervix, vulva, vagina, anus, penis), oropharyngeal cancers and skin cancers. The papillomavirus life cycle is strictly dependent on the terminal differentiation programme of the host cell – the keratinocyte. The virus deregulates host cell cycle control and inactivates the host cells' antiproliferative response in order to reprogramme the differentiating cells to support viral replication. In the case of high‐risk viruses, this is achieved by interactions with important tumour repressor pathways. Two prophylactic vaccines (Gardasil and Cervarix) are available to control infection by the most prevalent HPV types found in anogenital and oropharyngeal cancers.

Key Concepts

  • Papillomaviruses show strong species and tissue restriction and they share a similar genetic organisation.
  • Papillomaviruses are small double‐stranded (ds) DNA viruses that replicate as non‐integrated episomes in keratinocytes and are dependent on the keratinocyte undergoing terminal differentiation in order to complete their life cycle.
  • Low‐risk viruses such as HPV6 and 11 are associated with the formation of anogenital warts and laryngeal papillomaviruses that have a low risk of progression to cancer.
  • The most severe impact of human papillomavirus infection is the progression of a small proportion of infections to anogenital, oropharyngeal and skin cancers.
  • High‐risk viruses such as HPV16 and 18 are associated with infections of the mucosa lining the anogenital and oropharyngeal tract and HPV16 is the most prevalent genotype in cancers arising at these sites.
  • A majority of HPV infections are naturally eliminated by host‐cell‐mediated immunity and HPV infections are especially common in immunocompromised individuals (e.g. HIV‐infected patients, organ‐recipient patients, predisposing genetic conditions, e.g. epidermodysplasia verruciformis).
  • These viruses are a common sexually transmitted disease (STD) and infection in the oropharynx is most likely via an oral‐genital route.
  • High‐risk HPV early proteins E5, E6 and E7 are oncoproteins and the expression of E6 and E7 is retained in all cancers; E6 and E7 deregulate tumour suppressor pathways leading to host genomic instability.
  • Papillomaviruses replicate as extrachromosomal plasmids in the nulei of infected cells, but during cancer progression, the viral genome often becomes integrated into the host chromosome, resulting in a loss of the negative feedback control of viral oncogene expression by E2.
  • Prophylactic vaccines protect against infection with vaccine‐associated HPV types by inducing neutralising antibodies that recognise epitopes on the major capsid protein.

Keywords: human papillomavirus; animal papillomavirus; cervical cancer; head and neck cancer; viral oncogenes; E5; E6; E7; epidemiology; papillomas; genital warts; vaccines

Figure 1. Structure of papillomavirus virions. Electron micrograph of BPV‐1 particles (micrograph image reproduced with permission of Robert Garcea, University of Colorado, Colorado, US). The structure of one of the particles revealed by a three‐dimensional reconstruction to 9 Å. The virion is 60 nm in diameter and it is arranged in a T = 7 icosahedral lattice made from 72 L1 pentamers. The L1 protein can assemble spontaneously into structures that closely resemble native virions. The precise location of the L2 protein in the capsid is not fully known but most likely sits beneath each L1 pentamer and there are possibly up to 72 L2 molecules in each infectious particle (Buck et al., ). Reproduced from Roden RB, Greenstone HL, Vrhel M, Schiller JT, Booy FP (1997) Licensed under Public domain via Wikimedia Commons.
Figure 2. Papillomavirus life cycle is tightly linked to the terminal differentiation programme of keratinocytes. (a) Organisation of the double‐stranded DNA HPV genome. ORFs have been designated for the E (early) and L (late) viral genes, the non‐coding region designated LCR (long control region), the early promoter (PE), the late promoter (PL) activated in differentiating keratinocytes and the position of the early and late polyadenylation sites (pAE and pAL) are as indicated. In cancers, the papillomavirus genome is often integrated into the host DNA and the site of breakage in the viral DNA most often occurs in the region containing E1 and E2 ORFs (between the arrows). Integration leads to the disruption of expression of E2, which acts as a repressor of E6 and E7 expression. ORFs are coloured according to their timing of expression in the virus life cycle as shown in the schematic of the virus life cycle. (b) Schematic of the papillomavirus life cycle. Infectious virions enter the epithelium through microwounds and on reaching the basement membrane (BM) bind to heparin sulphate proteoglycans, which leads to a conformational change in the virus coat. This event exposes sequences of the minor capsid protein L2 that are then cleaved by the enzyme furin to facilitate binding of the capsid to a receptor on the cell cycle active basal keratinocyte (Kines et al., ). Following infection of the basal cells, the viral genome is established in the nucleus as a low copy extrachromosomal plasmid or episome. As the cell undergoes cell division, the viral genomes attach to the host chromosomes to ensure that they are segregated between daughter cells. The virally infected cell population expands as cell proliferation is activated at the same time as cells migrate upwards from the basal layer into the intermediate layers. Re‐entry of the differentiating cells into the cell cycle allows the virus to gain access to the host's replication machinery in order that the viral genome can be amplified to thousands of copies per cell. The virus prevents these replication‐activated cells from dying through apoptosis by blocking the host apoptotic pathways. Once the viral genome has amplified, the capsid proteins are expressed and virions assembled in the uppermost superficial cells and the infected squames, full of infectious particles, are sloughed off. The two panels (A and B) show cell cycle activity [as determined by expression of the nuclear cell cycle marker MCM7 (minichromosome maintenance protein 7), red stain, nuclei are stained blue] of cells in uninfected cutaneous skin (A) and HPV1‐infected wart tissue (B). In uninfected tissue, only cells of the basal layer (arrowheads) are cell cycle active, whereas in virally infected tissue, suprabasal cells (sb) also express MCM7 indicating S‐phase re‐entry.
Figure 3. Cutaneous hyperproliferative warts. (a) A typical common hand wart (verrucae vulgaris). Reproduced from Klaus D. Peter, Wiehl, Germany (2008)‐. Licensed under Creative Commons Attribution 3.0‐de via Wikimedia Commons (b) Haematoxylin and eosin‐stained section of common hand wart. Reproduced from Nephron ‐ Own work. Licensed under Creative Commons Attribution‐Share Alike 3.0 via Wikimedia Commons. Inset shows the appearance of koilocytes that are enlarged keratinocytes with pyknotic nuclei surrounded by a clear halo (examples are indicated with arrows) found in the upper layers of the wart. They are a recognised pathognomonic feature of papillomavirus infection.
Figure 4. HPV oncogenesis. The three oncoproteins E5, E6 and E7 work synergistically to promote hyperproliferation of infected cells, including the deregulation of the retinoblastoma (Rb) tumour suppressor pathway by E7 targeting the pocket proteins for degradation, deregulation of growth factor signalling pathways by E5 and E6 targeting cell polarity proteins containing PDZ domains. In response to aberrant cell proliferation, the host cell activates apoptotic pathways including those mediated by p53. To ensure survival of the infected cells, E6 inactivates the apoptotic response by targeting the tumour suppressor p53 protein for proteasomal degradation. In combination with activation of the host enzyme telomerase, which is necessary for the maintenance of telomeres, immortal cells can emerge. Continuous expression of the viral oncoproteins (integration of the viral DNA into the host leads also to upregulation of E6 and E7 expression) in the immortal cells leads to an unstable host genetic environment in which oncogenic mutations may occur and then clonal populations of fully transformed cells emerge. Adapted from Moody, CA., Laimins, LA. () ©Nature Publishing Group.


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Further Reading

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Roberts, Sally(Mar 2015) Papillomaviruses. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1002/9780470015902.a0000422.pub3]