Show Summary Details
Page of

Papillomaviruses and polyomaviruses 

Papillomaviruses and polyomaviruses
Chapter:
Papillomaviruses and polyomaviruses
Author(s):

Raphael P. Viscidi

and Keerti V. Shah

DOI:
10.1093/med/9780199204854.003.070519_update_001

May 30, 2013: This chapter has been re-evaluated and remains up-to-date. No changes have been necessary.

Update:

Viruses—four new human polyomaviruses were discovered using molecular techniques but no disease associations established.

Epidemiology—HPV-related oropharyngeal cancers expected to exceed the number of cervical cancers in the United States of America by 2020.

Merkel cell cancers—new epidemiological and molecular evidence for aetiological role of Merkel cell polyomavirus.

Updated on 31 May 2012. The previous version of this content can be found here.
Page of

PRINTED FROM OXFORD MEDICINE ONLINE (www.oxfordmedicine.com). © Oxford University Press, 2016. All Rights Reserved. Under the terms of the licence agreement, an individual user may print out a PDF of a single chapter of a title in Oxford Medicine Online for personal use (for details see Privacy Policy and Legal Notice).

Subscriber: null; date: 21 November 2019

Essentials

Papillomaviruses and polyomaviruses are small, nonenveloped, double-stranded DNA viruses.

Human papillomavirus

There are over 100 human papillomavirus (HPV) types that infect epithelia of skin and mucous membranes. They infect only humans, and cause conditions including the following:

Skin warts and verrucas—caused by types 1 and 2; infection initiated when, after e.g. minor skin abrasions, the basal cells of the epithelium come in contact with infectious virus.

Anogenital warts—caused by types 6 and 11; transmitted by direct sexual contact, these are the most common sexually transmitted infection; present clinically as multiple exophytic lesions or as subclinical flat lesions. Can be treated topically with podophyllin or imiquimod, or by ablative surgical methods. Recurrences are common. A highly efficacious prophylactic vaccine is available.

Cervical cancer—the second most common tumour in women worldwide; most often caused by types 16 and 18, whose DNA can be recovered from nearly all cases of invasive disease and squamous intraepithelial lesions of the cervix, which precede invasive cancer. Prevention is by cervical screening and vaccination (two highly effective vaccines are available).

Other cancers—HPVs can cause cancers at other lower anogenital tract sites and in the oropharynx. HPV DNA is often detected in nonmelanoma skin cancers, but it is not known whether this is pathogenic.

Respiratory papillomatosis—caused by types 6 and 11; usually involves the vocal cords, leading to presentation with hoarseness or voice change; may rarely cause life-threatening airway obstruction; mainstay of treatment is surgical removal of papillomas, which commonly recur.

Human polyomaviruses

Exposure to polyomaviruses is nearly universal: they cause asymptomatic infection in childhood and then persist as latent infections, primarily in the kidney, producing disease in the context of immunosuppression.

BK virus—can cause (1) nephropathy and renal failure in renal transplant patients; management is by gradual reduction in immunosuppression, but more than 50% of patients lose their allograft; (2) haemorrhagic cystitis in bone marrow transplant patients.

JC virus—causes progressive multifocal leucoencephalopathy, a demyelinating disease of the central nervous system that is usually relentlessly progressive and fatal. Most often seen in patients with HIV/AIDS, but recently reported as a rare complication of treatment with natalizumab in patients with multiple sclerosis or Crohn’s disease.

Merkel cell polyomavirus has recently been implicated as the aetiological agent of Merkel cell cancer, a rare aggressive skin tumour.

Introduction

Papillomaviruses and polyomaviruses are small, spherical, nonenveloped, doubled-stranded DNA viruses that multiply in the nucleus. The two virus groups are unrelated. Papillomaviruses infect surface epithelia and produce disease at these sites. Polyomaviruses are carried by viraemia, after initial multiplication at the site of entry, to affect internal organs such as the kidney and the brain. Viruses of both families produce experimental tumours in laboratory animals, but only papillomaviruses are related to naturally occurring cancers. Within each family the viruses are immunologically related and share nucleotide similarity.

More than 120 human papillomaviruses have been recognized, about 35 of which infect mucous membranes (genital and respiratory tracts, and the oral cavity) and the remainder infect skin. Human papillomaviruses cause skin warts, genital warts, respiratory papillomas, and papillomas at other mucosal sites (e.g. mouth, eye). In addition, infection with some genital tract human papillomaviruses causes cervical cancer, one of the most common female malignancies in the world, as well as a proportion of cancers at other genital tract sites and the oropharynx.

JC virus is the aetiological agent of progressive multifocal leukoencephalopathy, a fatal demyelinating disease occurring in immunodeficient people. BK virus is associated with haemorrhagic cystitis in bone marrow transplant recipients, and with nephropathy and renal failure in renal transplant recipients. Merkel cell polyomavirus is implicated as the aetiological agent of Merkel cell cancer, a rare aggressive skin tumour. Trichodysplasia spinulosa-associated polyomavirus is found in the rare skin disease of the same name and may play a role in the development of the disease. Several new human polyomaviruses have been identified recently using molecular techniques, but none of the viruses is known to cause disease.

Human papillomaviruses (HPVs)

Human papillomaviruses cannot be propagated in tissue culture and require nucleic acid hybridization assays for their identification. Their double-stranded circular genome contains about 8000 bp, divided into an early region, necessary for transformation, a late region, encoding for capsid proteins, and a regulatory region, containing control elements (Fig. 7.5.19.1). Open reading frames of the viral genome are located on one strand: E1 to E8 in the early region and L1 and L2 in the late region. The functions assigned to the different open reading frames are listed in Table 7.5.19.1.

Fig. 7.5.19.1 Genomic map of HPV-16. On the inner circle, P97 represents the transcriptional promoter and AE and AL designate early and late polyadenylation sites. The location of the early region open reading frames (E1–E8), the late region open reading frames (L1, L2), and of the long control or regulatory region (LCR) are shown.

Fig. 7.5.19.1
Genomic map of HPV-16. On the inner circle, P97 represents the transcriptional promoter and AE and AL designate early and late polyadenylation sites. The location of the early region open reading frames (E1–E8), the late region open reading frames (L1, L2), and of the long control or regulatory region (LCR) are shown.

(Reproduced from Shah KV, Howley PM (1996). Papillomaviruses. In: Fields BN, et al. (eds) Fields Virology, vol. 2, pp. 2077–109. Lippincott-Raven, Philadelphia., with permission.)

Table 7.5.19.1 Functions of human papillomavirus open reading frames

Function

ORF

Replication of viral DNA

E1, E2

Regulation of transcription

E2

Coding for late cytoplasmic protein

E4

Cellular proliferation

E5a

Transformation

E6, E7

Not known

E3, E8

Abbreviations: ORF, open reading frame.

a In bovine papillomavirus, the major transforming activity is in E5.

(Modified from Shah KV, Howley PM (1996). Papillomaviruses. In: Fields BN, et al. (eds) Fields Virology, vol. 2, pp. 2077–109. Lippincott-Raven, Philadelphia.)

Human papillomaviruses infect only humans. They show a marked degree of cellular tropism. Mucosal human papillomaviruses do not readily infect cutaneous epithelia and cutaneous human papillomaviruses are rarely present on mucous membranes. Infection is initiated when, after minor trauma (e.g. during sexual intercourse or after minor skin abrasions), the basal cells of the epithelium come in contact with infectious virus. The virus stimulates the proliferation of basal cells. The early region open reading frames are expressed in all layers of the infected epithelium, but expression of the late region open reading frames and synthesis of viral particles occur only in the upper differentiating and keratinizing layers.

Important disease associations and characteristics of mucosal HPVs are listed in Table 7.5.19.2. The burden of human cancers attributable to HPVs is shown in Table 7.5.19.3. The genital tract is the reservoir for all but a few mucosal human papillomaviruses and genital human papillomavirus infections constitute the most common viral sexually transmitted infections. Genital human papillomaviruses may sometimes infect nonanogenital mucosal sites, e.g. the respiratory tract, the mouth, and the conjunctiva. Transmission of genital tract HPV types 6 and 11 from an infected mother to the baby at birth results in juvenile onset recurrent respiratory papillomatosis. Infection with two types, HPV-13 and HPV-32, appears to be confined to the oral cavity.

Table 7.5.19.2 Mucosal human papillomaviruses: chief clinical associations

Clinical association

Viral type(s)

Exophytic condyloma; respiratory papillomas; oral and conjunctival papillomas

HPV-6, -11

Cervical cancer:

High-risk infections

HPV-16, -18, -31, -45, -33, -35, -39, -51, -52, -56, -58, -59

Low-risk infections

HPV-6, -11, -40, -42, -43, -44, -54, -61, -70, -72, -81

Vulval, vaginal, penile, anal, and oropharyngeal cancers

HPV-16

Focal epithelial hyperplasia of the oral cavity

HPV-13, -32

(Modified from Shah KV, Howley PM (1996). Papillomaviruses. In: Fields BN, et al. (eds) Fields Virology, vol. 2, pp. 2077–109. Lippincott-Raven, Philadelphia. Includes material from The Oxford textbook of medicine, 3rd edition, pp. 3366–9.)

Table 7.5.19.3 Cancers attributable to HPV infection in 2002

Site

Attributable to HPV (%)

Total cancers

Attributable to HPV

% of all cancers

Cervix

100

492 800

492 800

4.54

Penis

40

26 300

10 500

0.10

Vulva, vagina

40

40 000

16 000

0.15

Anus

90

30 400

27 300

0.25

Oropharynx

50

52 100

26 500

0.25

All sites

~5

10 862 500

(Modified from Parkin DM and Bray F (2006). The burden of HPV-related cancers. Vaccine 24, Suppl 3, S11–S25).

Table 7.5.19.4 lists disease associations of cutaneous HPVs, which are transmitted by direct contact with infected tissue or by contact with a contaminated object.

Table 7.5.19.4 Cutaneous human papillomaviruses: chief clinical associations

Clinical association

Viral type

Deep plantar wart

HPV-1

Common wart

HPV-2, -4

Mosaic wart (superficial spreading wart)

HPV-2

Flat warts

HPV-3, -10, -28, -41

Macular plaques of epidermodysplasia verruciformis

HPV-5, -8, -9, -12, -14, -15, -17, -19, -20, -21, -22, -23, -24, -25, -36, -47, -50

Squamous cell carcinoma

HPV-5,-8, -20, -36, -38

Modified from Shah KV, Howley PM (1996). Papillomaviruses. In: Fields BN, et al. (eds) Fields Virology, vol. 2, pp. 2077–2109. Lippincott-Raven, Philadelphia.)

Anogenital warts

Anogenital warts (condylomas) are the most commonly recognized clinical manifestations of genital HPV infections. More than 90% of condylomas result from infections with HPV-6 and HPV-11. In the United States of America, there are more than a million annual consultations for anogenital warts.

Epidemiology

Genital and anal warts are most common between the ages of 16 and 24 years. They are transmitted by direct sexual contact. Anogenital warts in children can also be due to close but nonsexual contact within a family but, in many cases, sexual abuse by an infected adult is responsible.

Clinical features

The incubation period is between 3 weeks and 8 months (mean=2.8 months). In men, condylomata acuminata (exophytic condylomas) most often appear on areas exposed to coital trauma, the glans penis, coronal sulcus, prepuce, and terminal urethra. The soft fleshy vascular tumours are usually multiple and may coalesce into large masses (Fig. 7.5.19.2). Sessile or papular warts are more likely to occur on dry areas such as the shaft of the penis (Fig. 7.5.19.3). The raised pink or grey lesions, 0.5 to 3 mm in diameter, may occur alone or with exophytic condylomas. Subclinical HPV lesions (flat condylomas) are identified by examining the genitalia with magnification after the application of 5% aqueous acetic acid solution. The affected areas are slightly raised and shiny white (acetowhite), with a rough surface. Flat condylomas affect the same areas as exophytic condylomas.

Fig. 7.5.19.2 Condylomata acuminata (exophytic condylomas) of the penis.

Fig. 7.5.19.2
Condylomata acuminata (exophytic condylomas) of the penis.

Fig. 7.5.19.3 Sessile (papular) warts of the penis.

Fig. 7.5.19.3
Sessile (papular) warts of the penis.

Perianal warts are usually exophytic and in moist conditions around the anus may reach a large size. In 50% of cases, condylomas also appear in the anal canal. Areas of acetowhite epithelium indicative of subclinical HPV infection may be associated with perianal warts or occur alone.

In women, exophytic condylomas (Fig. 7.5.19.4) appear at the fourchette and adjacent areas, and may spread to the rest of the vulva, the perineum, anus, vagina, and cervix. Multiple sessile warts may affect the labia and perineum. Subclinical HPV infection presents as slightly raised acetowhite lesions: the fissuring of these may cause dyspareunia. About 15% of women with vulval warts have exophytic condylomas on the cervix. Subclinical infection is more common, and consists of acetowhite lesions with punctation due to capillary loops, which can be identified by colposcopy. Large, exophytic vulval condylomas may develop during pregnancy and may become so large that they compromise delivery. Most regress post-partum.

Fig. 7.5.19.4 Condylomata acuminata of the vulva.

Fig. 7.5.19.4
Condylomata acuminata of the vulva.

Even with therapy (see below), recurrence of genital warts occurs within 3 months in 25 to 67% of cases. Recurrences are often at sites of previous genital warts and are attributed to persistent infection that then reactivates.

Diagnosis and management

Genital warts must be distinguished from Fordyce’s spots, fibroepithelial polyps, molluscum contagiosum, and the papillar lesions of secondary syphilis. Lesions that appear atypical or respond poorly to treatment must be biopsied early.

Associated sexually transmitted diseases must be excluded. Sexual partners should be examined. Intraepithelial neoplasia must be excluded. Cervical cytological examination should always be done on women with vulval warts and on female partners of men with penile warts.

Treatments for genital warts can be classified as topical, immunomodulatory, or surgical. Podophyllin and podophyllotoxin, which are derived from the root of the mayapple plant, are antimitotic agents that disrupt viral activity by inducing local tissue necrosis. Patient-applied topical podophyllotoxin, 0.5%, has a clinical cure rate of 56%; however, recurrence rates range from 23 to 65%. Disadvantages of podophyllin compounds include local adverse reactions, risk of systemic absorption, and teratogenicity. Imiquimod, a topical treatment for genital warts, induces macrophages to secrete cytokines, principally interferon-α‎, and is thought to work by stimulation of a cell-mediated immune response against HPV. Imiquimod is as effective as podophyllin for initial clearance of genital warts and results in a lower recurrence rate. The side effect profile of imiquimod is benign. Warts may be destroyed by cryotherapy with liquid nitrogen, electrocautery, electrodessication, scissor excision, or carbon dioxide laser therapy. Although these ablative therapies are successful in initially removing genital warts, recurrences are common. In a comparative trial, imiquimod 5% cream alone or in combination with ablative treatments was superior to ablation alone in reducing the recurrence rate of successfully treated anogenital warts. A prophylactic vaccine that prevents 100% of genital warts due to HPV-6 and HPV-11, if administered prior to exposure to HPV, is now commercially available in many countries (see below).

Respiratory papillomatosis

This rare disease may have onset in childhood or in adult life. It is most common in children under the age of 5 years. It may become life-threatening if it obstructs the airways. Papillomatosis usually involves the vocal cords and the patient presents with hoarseness or voice change. Papillomas may recur after surgical removal.

HPV-6 and HPV-11, genital tract HPVs that are responsible for most of the exophytic genital warts, also cause respiratory papillomatosis. Patients with juvenile-onset disease are infected at birth during passage through an infected birth canal. In adult-onset disease, transmission may occur by sexual contact. Respiratory papillomas rarely progress to invasive cancer. Irradiation of papillomas with X-rays (a practice now discontinued) increases the risk of malignancy.

Caesarean delivery for mothers who are found to have genital warts or are infected with HPV-6 or HPV-11 would reduce the risk of juvenile-onset respiratory papillomatosis, but it is not generally recommended because of the small risk of disease following perinatal infection. The mainstay of treatment is surgical removal of papillomas; however, recurrence of lesions is common. Various adjunct therapies have been tried, including interferon-α‎, indole-3-carbinol, cidofovir, and photodynamic treatment. These therapies have had only modest success in reducing the need for surgery. It is anticipated that a child born to a mother who has received the HPV Gardasil vaccine, will have a markedly reduced risk of developing respiratory papillomatosis.

Cervical cancer

(Chapter 6.1)

Human papillomavirus DNA is recovered from nearly 100% of cases of invasive cervical cancer and squamous intraepithelial lesions of the cervix, which precede invasive cancer. The viral genome is present in the tumour cells of primary as well as metastatic cervical cancer. The progression from low grade squamous intraepithelial lesions to invasive cancer may take more than 10 years; human papillomaviruses are found throughout this disease process. The viruses are recovered much less frequently from cytologically normal women of comparable age. In prospective studies of women with normal cervical cytology, the presence of HPV is a strong risk factor for the subsequent development of squamous intraepithelial lesions.

Certain HPV types are preferentially associated with invasive cancers. From their distribution in normal individuals and in preinvasive and invasive cervical disease, genital tract HPVs have been categorized as high-risk, or low-risk types (Fig. 7.5.19.5; Table 7.5.19.2). HPV-16 and HPV-18 are the predominant viruses in invasive cancers and account for 40 to 60% and 5 to 20%, respectively, of HPV-positive cancers in different studies. About a dozen additional types of HPV are found in small proportions of invasive cancers. The low-risk HPVs are almost never detected in invasive cervical cancers.

Fig. 7.5.19.5 Percentages of cervical cancer cases attributed to the most frequent HPV types in all world regions combined. X includes the rare types 40, 42, 53, 54, 55, 83, and 84. ‘Unk’ includes specimens that were positive for HPV DNA but could not be genotyped by current methods.

Fig. 7.5.19.5
Percentages of cervical cancer cases attributed to the most frequent HPV types in all world regions combined. X includes the rare types 40, 42, 53, 54, 55, 83, and 84. ‘Unk’ includes specimens that were positive for HPV DNA but could not be genotyped by current methods.

(Data from Munoz N, et al. (2004). Against which human papillomavirus types shall we vaccinate and screen? The international perspective. Int J Cancer, 111, 278–85.)

Comparisons of different HPV types for their ability to transform human keratinocytes in vitro show that HPV-16 and HPV-18, types most clearly associated with naturally occurring cervical cancers, also have the greatest oncogenic potential in laboratory studies. The transforming functions of HPVs are localized to open reading frames E6 and E7; these are the viral genes consistently expressed in naturally occurring HPV-positive cancers. The viral genome is integrated into the cellular DNA in most cervical cancers. The break in the circular viral genome that is required for integration occurs most frequently in the E1/E2 region and results in an enhanced expression of the transforming E6 and E7 open reading frames. The transforming HPV proteins E6 and E7 interact with cellular tumour suppressor proteins p53 and Rb, respectively. The oncogenic effect of HPVs is mediated largely by their ability to inactivate the tumour suppressor proteins which normally regulate the cell cycle.

Epidemiology

Human papillomavirus infections of the genital tract are extremely common in sexually active populations. In young sexually active women, point prevalence (single sampling) of HPV infection as measured by the detection of HPV DNA in genital tract specimens by the sensitive polymerase chain reaction (PCR) may be as high as 40%, and the cumulative prevalence (multiple sampling of women over time) may be as high as 80 to 90%. The prevalence decreases with increasing age. Most of these infections are found in women with normal cervical cytology and undoubtedly resolve without leaving a trace. Only a small proportion of infections persists and progresses to squamous intraepithelial lesions and then to invasive cancer. The cofactors that might be associated with progression to cancer include smoking, use of oral contraceptives, parity, and presence of other sexually transmitted diseases. Human immunodeficiency virus (HIV) infection and associated immunosuppression, leads to a much higher prevalence, and longer persistence, of HPV infections and to greater incidence of squamous intraepithelial lesions.

Prevention and control

Screening for cervical cytological abnormalities by cervical smear and treatment of preinvasive and invasive cancers identified by screening, have been credited with the decrease in incidence of cervical cancer and mortality due to the disease that has been observed in many developed countries over the last 40 to 50 years. Women who have cytological abnormalities which are low grade or of uncertain significance may benefit from an HPV diagnosis. The presence of cancer-associated HPVs would indicate a need for closer monitoring and colposcopy; HPV-negative women would be monitored routinely. Tests for the presence of high risk HPVs may replace cervical smears as cervical cancer screening strategy.

Prophylactic vaccines

The discovery that the L1 coat protein of papillomaviruses could assemble into a virus-like particle (VLP), when expressed as a recombinant protein, and the demonstration that immunization of rabbits, cattle, and dogs with VLPs of their respective papillomaviruses protected against papillomavirus-induced disease, stimulated the development of vaccines for human papillomaviruses. L1 VLPs appear to induce very limited cross-neutralization against other genotypes necessitating a multicomponent vaccine to provide coverage against disease caused by more than one type. Two HPV L1 VLP vaccines have been developed commercially; Cervarix is a bivalent HPV-16/18 L1 VLP vaccine and Gardasil is a quadrivalent HPV16/18/6/11 L1 VLP vaccine. Both vaccines are generally safe and well tolerated and are highly immunogenic. Both vaccines have demonstrated truly remarkable efficacy, preventing nearly 100% of incident infections and preinvasive cervical cancers due to the HPV types in the vaccines. Gardasil is also 100% effective in preventing genital warts associated with HPV 6/11. Since genital HPV infection is sexually transmitted, the vaccines ideally should target prepubertal and young adolescent girls. The vaccines are also recommended for young women 13 to 26 years of age, because many of them may not yet have been exposed to the HPV types in the vaccines. If HPV vaccines are proven to be safe and efficacious in males, future recommendations will likely include immunization of boys and young men in order to reduce the risk of genital warts, protect against penile and oropharyngeal cancer, and provide herd immunity. The durability of the immune response engendered by HPV vaccines and thus the possible need for a booster in vaccinated individuals is unknown. Because protection may wane over time and because vaccination does not protect against the HPV types not included in the vaccines, screening programmes will need to be maintained, but the strategy may change with longer intervals between screening and a greater emphasis on HPV DNA testing as a screening method.

Therapeutic vaccines

Human papillomavirus-associated cancers express HPV E6 and E7 proteins in their tumour cells. Candidate therapeutic vaccines targeted to these proteins are being developed for the treatment of high grade squamous intraepithelial lesions and invasive cancer.

Cancers at other lower anogenital tract sites

Human papillomavirus infections are very common on the vulva, vagina, penis, perineum, and anus. Synchronous neoplasia at multiple sites in the female lower genital tract is almost always associated with HPVs, especially HPV-16. Carcinoma of the vulva is aetiologically heterogeneous. Vulval cancers occurring in younger women are associated with HPVs, but the typical squamous cell carcinoma of the vulva in older women is not. Neoplasia of the anal canal, seen frequently in HIV-seropositive homosexual men, is strongly associated with HPVs.

Cancer of the oropharynx

A subset of oropharyngeal cancers, especially tonsillar cancers, is aetiologically linked to high-risk HPVs, most often HPV-16. Patients with HPV-associated cancers have risk factors related to their sexual history rather than to alcohol and tobacco use. As compared to HPV-negative cancers, the HPV-positive cancers are characterized by more frequent basaloid pathology, less frequent p53 and Rb mutations, and better prognosis. Demonstration of HPV genome in tumour cells, presence of HPV transcripts, and immunostaining for cellular p16 characterize HPV-caused cancers, which are increasing in incidence in North America and Europe. It is estimated that the number of HPV-caused oropharyngeal cancers in men and women will exceed the number of cervical cancers in the United States of America by 2020.

Skin warts

(Chapter 23.10)

Skin warts and verrucas may occur anywhere on the skin and are morphologically diverse. They are most common in older children and young adults. Except in the rare condition known as epidermodysplasia verruciformis (see below), they almost never become malignant. Most regress within 2 years. Specific HPV types are strongly associated with specific types of warts (Table 7.5.19.4).

Epidermodysplasia verruciformis

This is a rare, lifelong disease in which a patient has extensive warty involvement of the skin that cannot be resolved. It generally begins in infancy or childhood with multiple, disseminated polymorphic wart-like lesions on the face, trunk, and extremities that tend to become confluent. The warts are either flat or reddish-brown macular plaques that resemble pityriasis versicolor. In about a third of the cases, foci of malignant transformation occur in macular plaques in areas of the skin exposed to sunlight. The tumours are slow growing and rarely metastasize.

Epidermodysplasia verruciformis (EV) is often a familial disease. Patients sometimes have a history of parental consanguinity. A susceptibility locus has been mapped to chromosome 17q25 and truncating mutations in either of two novel adjacent genes, TMC6 and TMC8, are associated with the disease in different pedigrees. The function of the gene products of TMC6 and TMC8 and how they confer increased risk for EV are unknown. A second putative susceptibility locus is located on chromosome 2p21-p24. The flat warts yield the same HPV types as those of normal individuals, but a very large number of HPVs that are seldom encountered in normal individuals are recovered from the macular plaques (Table 7.5.19.3). It is unclear how patients with epidermodysplasia verruciformis become infected with these particular papillomaviruses. The factors that contribute to the occurrence of carcinoma in these patients therefore include a genetic defect, infection with specific HPVs, e.g. HPV-5 and HPV-8, and exposure of the affected area to sunlight.

Nonmelanoma skin cancers

HPV DNA has been detected in 30 to 50% of nonmelanoma skin cancers (NMSC) in immunocompetent populations and in up to 90% of NMSC from immunocompromised populations, in particular organ transplant recipients. The HPV prevalence is generally higher in squamous cell carcinoma than in basal cell carcinoma. The sequences represent cutaneous HPV types, EV-associated HPVs, and many novel HPV sequences. No single HPV type predominates and there is no evidence of high-risk types analogous to those seen in cervical cancer. The amount of HPV DNA in skin tumours is very low, indicating that not every tumour cell harbours an HPV genome. Because HPV DNA is frequently detected in normal skin samples, it is not clear to what extent HPVs contribute to the development of NMSC. Ultraviolet (UV) light is considered the most significant risk factor for NMSCs. Cutaneous HPVs through the antiapoptotic activity of their E6 gene may act as cocarcinogens by preventing elimination of cells with UV-induced DNA damage.

Human polyomaviruses

In 1971, BK virus was isolated from the urine of a renal transplant recipient and JC virus was recovered from the brain of a patient with progressive multifocal leukoencephalopathy. Recently, two new human polyomaviruses, KI virus and WU virus, were detected in respiratory tract secretions of children by using molecular techniques. The viruses were detected in upper respiratory tract specimens in the presence of other recognized respiratory tract pathogens and thus their role in disease is unclear. In 2008, another new human polyomavirus, Merkel cell virus, was identified in tumour cells from patients with Merkel cell carcinoma, a rare aggressive skin cancer.

Papillomaviruses and polyomavirusesTrichodysplasia spinulosa (TS) is a rare skin disease primarily affecting immunosuppressed patients and presenting as follicular-based papules and keratin spicules widespread on the face, along with variable degrees of alopecia and dysmorphism. In 2010, a new human polyomavirus, designated TS-associated polyomavirus, was identified in the TS lesions of a heart transplant recipient. Two new human polyomaviruses, designated type 6 and 7, were detected in the skin of healthy persons. Another new human polyomavirus, type 9, was identified in the blood and urine of a renal transplant patient. Subsequently the virus was independently identified in the skin of a Merkel cancer patient. No diseases have been associated with polyomavirus types 6, 7, and 9. All the new polyomaviruses were detected by using a variety of molecular techniques that do not rely on prior knowledge of the DNA sequence of the virus.

Polyomaviruses have a double-stranded DNA genome of about 5000 bp, which is divided into an early region encoding viral T proteins, a late region encoding viral capsid proteins, and a noncoding regulatory region. The T proteins regulate viral transcription, initiate viral DNA replication, and mediate inactivation of host cell tumour suppressor proteins, which contribute to the oncogenic potential of polyomaviruses. The viral regulatory region contains elements for viral DNA replication and promoters for transcription of early and late genes, as well as binding sites for cellular transcription factors, which determine the host and tissue tropism of polyomaviruses.

The early and late regions are transcribed from different strands of the viral DNA. Although BK and JC viruses are homologous for 75% of their nucleotide sequence, the infections are readily distinguishable by conventional tests.

Infection occurs in childhood and is largely subclinical. Most children acquire antibodies to BK virus by the age of 10; infection with JC virus occurs at a later age. Infection occurs by the respiratory route and possibly by ingestion. Both viruses establish latent, often lifelong, infection in the kidney and are often shed in the urine of normal people. Reactivation in immunodeficient people is responsible for most associated illnesses. The viruses are reactivated in pregnancy, but without any apparent harm to the mother or the newborn.

Polyomavirus-associated illnesses

Nephropathy in renal transplant recipients

This condition is associated most often with BK virus and rarely with JC virus. It occurs in 3 to 10% of renal transplant recipients and results in a loss of the allograft in 50 to 80% of the affected patients. The recent increase in the incidence of this complication is related to the introduction of new and intensive immunosuppressive therapies. Pathologically, the disease is characterized by inclusion-bearing enlarged nuclei in renal tubular and glomerular epithelial cells which are readily detected by microscopy (Fig. 7.5.19.6). Monitoring of the patients for BK virus viraemia has predictive value for the incidence of the disease.

Fig. 7.5.19.6 BK virus infected cells (dark and hyperchromatic) in renal parenchyma, with some cells shed in the tubular lumen.

Fig. 7.5.19.6
BK virus infected cells (dark and hyperchromatic) in renal parenchyma, with some cells shed in the tubular lumen.

Haemorrhagic cystitis in bone marrow transplant recipients

Late-onset haemorrhagic cystitis in bone marrow transplant recipients is associated with BK virus infection. Large amounts of BK virus are shed in urine during the haemorrhagic episodes.

Progressive multifocal leucoencephalopathy (PML)

(Chapters 7.5.23 and 24.11.2)

JC virus causes progressive multifocal leucoencephalopathy, a subacute demyelinating disease of the central nervous system occurring in individuals with impaired cell-mediated immunity. Until the advent of AIDS, it was a rare disease found mainly in older patients with lymphoproliferative disorders or chronic diseases. Because PML is a complication in 1 to 2% of AIDS cases, it is a more common disease and is seen much more frequently in younger patients. It has also been recognized in children who have inherited immunodeficiency diseases or have AIDS. Recently, PML has been recognized as a complication in patients with Crohn’s disease or multiple sclerosis participating in clinical trials of natalizumab monoclonal antibody, which inhibits migration of cells across the blood–brain barrier.

The key pathogenetic event in PML is the cytocidal JC virus infection of oligodendrocytes, which are responsible for the production and maintenance of myelin. This leads to foci of demyelination that tend to coalesce and eventually involve large areas of the brain. Infected oligodendrocytes, containing large inclusion-bearing nuclei filled with abundant virus particles, surround the foci of demyelination (Fig. 7.5.19.7). Enlarged astrocytes often show bizarre nuclear changes but are mostly virus negative. They are found within the foci of demyelination. JC virus is disseminated haematogenously to the central nervous system, probably through virus-infected B lymphocytes.

Fig. 7.5.19.7 A lesion of progressive multifocal leukoencephalopathy showing oligodendrocytes with enlarged, deeply staining nuclei (arrow) and giant astrocytes (left), and a crystalloid array of JC virus particles in an infected oligodendrocyte nucleus (right).

Fig. 7.5.19.7
A lesion of progressive multifocal leukoencephalopathy showing oligodendrocytes with enlarged, deeply staining nuclei (arrow) and giant astrocytes (left), and a crystalloid array of JC virus particles in an infected oligodendrocyte nucleus (right).

(Reproduced, with permission, from Shah KV (1992). Polyomavirus, infection and immunity. In: Roitt IM (ed) Encyclopedia of Immunology, pp. 1256–8. Academic Press, New York.)

PML starts insidiously. Early signs and symptoms indicate the presence of multifocal asymmetrical lesions in the brain and involve impairment of vision and speech, and mental deterioration. The disease is usually relentlessly progressive and fatal within 3 to 6 months, but rarely it can become stabilized with survival for many years. CT and MRI have been successfully used for diagnosis (Fig. 7.5.19.8). Treatment with cytosine arabinoside and the presence of an inflammatory response in the brain have been associated with the few relatively successful outcomes.

Fig. 7.5.19.8 Brain fluid attenuation inversion recovery (FLAIR) MRIs in axial (a) and sagittal (b) planes of a 36-year-old man with AIDS and progressive multifocal leukoencephalopathy proven by detection of JC virus DNA in cerebrospinal fluid by PCR.

Fig. 7.5.19.8
Brain fluid attenuation inversion recovery (FLAIR) MRIs in axial (a) and sagittal (b) planes of a 36-year-old man with AIDS and progressive multifocal leukoencephalopathy proven by detection of JC virus DNA in cerebrospinal fluid by PCR.

Role of polyomaviruses in human tumours

The role of polyomaviruses in human tumours is the subject of debate. JC virus and BK virus are oncogenic for laboratory animals and they transform cultured cells. There are reports of finding JC virus DNA in brain and colon tumours and BK virus DNA in prostate, bladder, and brain tumours, as well as neuroblastomas and insulinomas. However, a reproducible and consistent aetiological association of either virus with any human tumour has not been demonstrated. The Merkel cell virus provides a more convincing example of a polyomavirus-induced human tumour, since the viral genome was found to be integrated into tumour cell DNA, a key event in experimental polyomavirus-induced animal tumours. Further supporting the carcinogenic potential of the virus is the observation that survival of virus-positive Merkel cancer cell lines is dependent on expression of the viral oncoprotein. The virus has been detected in approximately 80% of Merkel cell cancers worldwide. Serological studies have revealed that exposure to Merkel cell polyomavirus is very high in human populations. Thus, the precise role of the virus and modifying cofactors in the aetiology of Merkel cell carcinoma remains to be established.

Further reading

Berger JR, et al. (1998). Progressive multifocal leukoencephalopathy in patients with HIV infection. J Neurovirol, 4, 59–68.Find this resource:

Bosch FX, et al. (2002). The causal relation between human papillomavirus and cervical cancer. J Clin Pathol, 55, 244–265.Find this resource:

Chatuevedi AK, et al. (2002). Human papillomavirus and rising oropharyngeal cancer incidence in the United States. J Clin Oncol, 29, 4294–301.Find this resource:

    D’Souza G, et al. (2007). Epidemiological evidence that human papillomavirus is a cause of oropharyngeal squamous cell carcinomas. N Engl J Med, 356, 1944–56.Find this resource:

    Koutsky LA, et al. (2002). A controlled trial of a human papillomavirus type 16 vaccine. N Engl J Med, 347, 1645–51.Find this resource:

    Munoz N, et al. (2004). Against which human papillomavirus types shall we vaccinate and screen? The international perspective. Int J Cancer, 111, 278–85.Find this resource:

    Randhawa P, Brennan DC. (2006). BK virus infection in transplant recipients: an overview and update. Am J Transplant, 6, 2000–5.Find this resource:

    Shah KV. (1992). Polyomavirus, infection and immunity. In: Roitt IM (ed) Encyclopedia of immunology, pp. 1256–8. Academic Press, New York.Find this resource:

      Shah KV, Howley PM. (1996). Papillomaviruses. In: Fields BN, et al. (eds) Fields virology, vol. 2, pp. 2077–109. Lippincott-Raven, Philadelphia.Find this resource:

        Yousry TA, et al. (2006). Evaluation of patients treated with natalizumab for progressive multifocal leukoencephalopathy. N Engl J Med, 354, 924–33.Find this resource: