PAPOVAVIRIDAE

The family Papovaviridae comprises two genera: (1) the genus Papillomavirus, and (2) the
genus Polyomavirus. The first two syllables of the name Papovaviridae refer to the genera
Papillomavirus and Polyomavirus; "va" alludes to "vacuolating agent," an old name for the
prototype polyomavirus, simian virus 40 (SV40).

a papillomavirus capsid Schematic diagram representing Negative contrast electron

with combined image the 72 capsomers of a
micrograph of human
reconstructions from papillomavirus capsid (the
PAPILLOMAVIRUSES papillomavirus 1 (HPV-1)
electron cryomicroscopy of icosahedral structure includes 360
VP1 subunits arranged in 12 virions. The bar represents 100
bovine papillomavirus
pentavalent and 60 hexavalent
capsomers).

(1) The primary infection occurs in a cell of the striatum germinativum, with the virus gaining entry
via an abrasion, etc. (2) This results in a proliferating clone of infected cells that spreads laterally in
association with virus-induced delay in the maturation of infected cells. (3) Cellular differentiation
occurs eventually and large numbers of virions are produced in association with the formation of a
papilloma. This is most pronounced in the stratum granulosum. Virions are shed with exfoliated cells
of the stratum corneum.

PAPILLOMAVIRUS
Papillomavirus virions are nonenveloped, spherical, 55 nm in diameter, with icosahedral
symmetry. Virions are composed of 72 hexavalent (6-sided) capsomers arranged in pentameric
(5-sided) arrays. The genome consists of a single molecule of circular double-stranded DNA,
6.8-8.4 kb in size. Papillomaviruses are resistant to diverse environmental insults and infectivity
survives lipid solvents and detergents,

Immunoperoxidase staining of
papillomavirus capsid antigen in only
the superficial layers of the infected
PAPILLOMAVIRUSES OF CATTLE

Papillomavirus-induced papillomas and fibropapillomas are recognized more commonly in cattle

than in any other domestic animal. All ages can be affected, but the incidence is highest in
calves and yearlings.

a. genus Deltapapillomavirus – BPV – 1, 2, 13 & 14

b. genus Xipapillomavirus – BPV – 3, 4, 6,9,10, 11 & 12
c. genus Epsilonpapillomavirus – BPV – 5 & 8
d. genus Dyoxipapillomavirus – BPV - 7

Papillomaviruses are probably transmitted between animals by fomites, including contaminated

milking equipment, halters, nose leads, grooming and earmarking equipment, rubbing posts
and wire fences, and other articles contaminated by contact with affected cattle. It is likely that
sexual transmission of papillomavirus-induced genital papillomas (venereal warts) occurs in
cattle, as such lesions are rare in animals that are artificially inseminated. Teat and udder
papillomas are common in dairy cattle, presumably due to transmission during milking.
Papillomas are more common in housed cattle than in cattle on pasture.

Infection of epithelial cells results in hyperplasia and hyperkeratinization, usually within 6 weeks
of exposure. In general, papillomas persist for 1-6 months before spontaneous (immune-
mediated) regression; multiple warts usually regress simultaneously. Rarely, florid persistent
infections can occur and cause morbidity or mortality by interfering with vision or predisposing
to fly strike or bacterial infection.

Two subtypes of Papilloma

a. Squamous papillomas
 typically develop in the mucocutaneous areas except those caused by BPV-4,
which develop in the caudal oral cavity, esophagus, and rumen
 tend to be flat with a broad base
 Histologic features of a squamous papilloma include an extensively thickened
folded epithelium with evidence of productive papillomavirus replication (eg,
“koilocytes”) overlying a typically normal dermis
b. Fibropapillomas
 caused by BPV-1, -2, and possibly -5 infections
 common on the udder and teats and on the head, neck, and shoulders; they may
also occur in the upper alimentary tract, vagina, vulva, penis, and anus
  typically, exophytic or pedunculated and vary from small firm nodules to large
cauliflower-like growths; they are grayish to black in color and rough and spiny
to the touch
 Large masses are subject to abrasion and may bleed.
 Histological features of a fibropapilloma include a proliferation of dermal
fibroblasts that form a fibrous core covered by hyperplastic epithelium

Bovine papillomas. Despite the large numbers of papillomas,

this cow exhibited few other signs of disease.

PAPILLOMAVIRUSES OF HORSES

Equine papillomaviruses cause cutaneous papillomas, aural plaques, genital papillomas, and are
increasingly causally associated with penile and preputial squamous cell carcinomas. Most
cutaneous papillomas are thought to be caused by EcPV-1 (Equus caballus papillomaviruses 1)
and are usually small, elevated, keratinized lesions that are most common around the lips and
nose of young horses, but can also occur on the ears, eyelids, and limbs. They generally
regress within 9 months.

Aural plaques are predominantly associated with infection by EcPV-3 and -4, although EcPV-5
and -6 may also be potential causes. Aural plaques are discrete, raised, smooth or roughened
pale plaques or nodules on the inner surface of the pinnae of the ear. The plaques are neither
pruritic nor painful, however, unlike cutaneous papillomas, they do not spontaneously regress.

Genital papillomas are predominantly caused by EcPV-2. Papillomas can develop singularly, but
multiple papillomas or extensive papillomas covering much of the penis (papillomatosis) is also
common. Papillomas do not appear to cause discomfort to the horse and their major
significance is their predisposition to progress to squamous cell carcinomas.

Penile and preputial squamous cell carcinomas are relatively common cancers of horses. These
squamous cell carcinomas can develop from genital papillomas and penile squamous cell
carcinomas more frequently contain EcPV-2 DNA, and in higher copy numbers, than unaffected
(nonneoplastic) equine penile tissue.
EQUINE SARCOID

Equine sarcoids are caused by bovine deltapapillomaviruses BPV-1, -2, or -13. Sarcoid is the
most common skin tumor of horses, mules, and donkeys. Sarcoids are most common in horses
less than 4 years of age, and may occur singly or in groups, with a predilection for the head,
ventral abdomen, and limbs. Clinical types of sarcoids include verrucous (wart-like), fibroblastic,
mixed, and flat. Histologically, equine sarcoids consist of proliferating, haphazardly-arranged
fibroblasts covered by typically hyperplastic epithelium that has characteristic thin frond-like
extensions into the dermal mass.

Numerous treatments including surgical excision, cryotherapy, hyperthermia, chemotherapy,

radiation therapy, antiviral treatments, and immunomodulation have all been suggested to treat
equine sarcoids. Unfortunately, recurrence is common regardless of the treatment and equine
sarcoids can be frustrating to treat.

PAPILLOMAVIRUSES OF DOGS

Sixteen papillomaviruses from three different genera have been reported in domestic dogs, with
Canis familiaris papillomavirus (CPV) types 1 and 6 included in the genus
Lambdapapillomavirus, CPV types 2, 7, and 13 in the genus Taupapillomavirus, and the
remainder in the genus Chipapillomavirus. Diseases caused by papillomaviruses in dogs include
oral papillomas, cutaneous papillomas, and cutaneous pigmented plaques.

a. Oral papillomas
 caused by CPV-1 (formerly canine oral papillomavirus) and, possibly, CPV-13
 the most common papillomavirus-induced disease of dogs
  Affected dogs are typically young and present with multiple, exophytic oral
lesions. Warts usually first develop on the lips, but can spread to the buccal
mucosa, tongue, palate, and pharynx.
 Histologic features of these lesions include epithelial hyperplasia with prominent
cytopathologic features consistent with papillomavirus infection.
 Papillomas develop 4-8 weeks after infection with most lesions typically
regressing within 8 weeks.
b. Canine cutaneous papillomas
 are most often caused by CPV-2, although involvement by CPV-6 has also been
reported.
 occur most commonly on the feet of young dogs
 They can develop within nailbed epithelium, causing distortion of the claw and
destruction of the underlying bone.
 skin trauma and immunosuppression appear to predispose to papilloma
development.
 subclassified as exophytic, which are histologically similar to papillomas in other
species, or inverted
 Inverted papillomas consist of discrete dermal cup-shaped structures lined by a
thickened epidermis that exhibits changes typical of papillomavirus infection.
 Both exophytic and inverted papillomas typically spontaneously regress although
there are rare reports of progression of a papilloma to squamous cell carcinoma.
c. Canine cutaneous pigmented plaques
 These are single or, more frequently, multiple dark raised plaques that typically
occur on the ventrum.
 They are most common in pugs, but have been reported in many breeds of dog.
 Histologically, cutaneous pigmented plaques appear as a well-defined focus of
epithelial hyperplasia with large quantities of melanin within the deeper layers of
the epidermis and within the superficial dermis. Most plaques do not contain
keratinocytes that exhibit characteristic papillomavirus-induced cell changes. The
major clinical significance of canine pigmented plaques is their rare progression
to squamous cell carcinomas

Oral papillomas in a dog

PAPILLOMAVIRUSES OF CATS

Four different Felis catus papillomaviruses (FcaPVs) have been fully sequenced from domestic
cats, including members of the genera Lambdapapillomavirus (FcaPV-1),
Dyothetapapillomavirus (FcaPV-2), and Taupapillomavirus (FcaPV-3 and 4).
Feline oral viral papillomas are caused by FcaPV-1 and appear as pale sessile lesions on the
ventral surface of the tongue. The cause of cutaneous viral papillomas is currently unknown,
although one papilloma contained a DNA sequence from a human papillomavirus type. Other
diseases that are recognized to be caused by papillomaviruses in cats include feline viral
plaques, Bowenoid in situ carcinomas (BISCs), and feline sarcoids.

FcaPV-2 is associated with the majority of papillomavirus-induced disease of cats, and causes
both cutaneous viral plaques and BISCs. Viral plaques and BISCs are similar but uncommon skin
lesions of cats that typically appear as single or multiple raised hairless plaques that can be pale
or pigmented. Viral plaques and BISCs have a variable clinical course with some lesions
resolving or remaining static for years and other lesions continuing to develop to become
extensive over the skin of the cat or even progressing to an invasive cancer.

FcaPV-2 may contribute to the development of feline cutaneous squamous cell carcinomas.
Squamous cell carcinomas are common in cats and evidence that they are caused by
papillomavirus infection includes the frequent detection of viral sequences in the cancers and
the detection of changes in cell regulatory proteins that indicate a papillomavirus etiology in
similar human cancers.

Feline Bowenoid in situ carcinoma. Note the presence of

numerous raised plaques on this hairless breed of cat.

FELINE SARCOID

Feline sarcoids are dermal fibroblastic proliferations that occur most often in young cats, on the
head, neck, and digits. These tumors have a similar histologic appearance and clinical behavior
to equine sarcoids. Also consistent with equine sarcoids, a bovine papillomavirus is the likely
causative agent. However, the papillomavirus type that appears to cause feline sarcoids, BPV-
14, is distinct from the bovine papillomavirus types that cause equine sarcoids. Not surprisingly,
feline sarcoids are almost invariably seen in cats from rural areas that have contact with cattle.

PAPILLOMAVIRUSES OF OTHER MAMMALIAN SPECIES

a. Sylvilagus floridamus papillomavirus type 1 (also called cottontail rabbit papillomavirus

and Shope papillomavirus) is notable as this was the first papillomavirus shown to cause
cancer.
b. papillomavirus (Oryctolagus cuniculus papillomavirus 1 or rabbit oral papillomavirus)
results in self-resolving papillomas which most frequently appear as gray-white, filiform
or pedunculated nodules (5 mm in diameter) on the underside of the tongue, and less
often, the lips.
c. Castor Canadensis Papillomavirus type 1 which infects beaver is unique in that the virus
could be propagated in vitro in rabbit and feline cells.
PAPILLOMAVIRUSES OF NONMAMMALIAN SPECIES

a. Birds
 papillomaviruses have been shown to cause papillomas in wild common chaffinch
(Fringilla coelebs), brambling (Fringilla montifringilla), and Eurasian bullfinch
(Pyrrhula pyrrhula). Papillomas occur exclusively on the toes and distal legs, and
show stages of development from a slight node on a digit to heavy involvement
of the foot and adjacent regions, with obscuring of the individual digits and
resulting overgrowth and distortion of the claws.
 Different papillomavirus types have also been detected in papillomas of African
grey parrots (Psittacus erithacus) and healthy skin of a yellow-necked Francolin
(Francolinus leucoscepus).
b. Reptiles
 Papillomaviruses have also been detected in cutaneous papillomas in reptiles,
including Diamond pythons (Morelia spilota spilota) and in Loggerhead (Caretta
caretta) and Green (Chelonia myda) sea turtles.

POLYOMAVIRUSES
Polyomaviruses have small, circular, double-stranded DNA genomes encapsulated in icosahedral
virions. Virions are generally smaller (40-45 nm) than those of papillomaviruses and the
genome of polyomaviruses (approximately 5 kb) is also smaller than those of papillomaviruses.

Although the replication strategy of polyomaviruses is similar to that of papillomaviruses, the

transcription of coding regions occurs on opposite DNA strands in the case of polyomaviruses
and on the same strand with papillomaviruses.

The polyomaviruses have a remarkable range of tissue tropism and have been reported to
cause neurologic, renal, and skin diseases. The severity of disease caused by polyomaviruses is
also highly variable, with birds infected with the polyomaviruses often developing acute,
systemic, and cytolytic disease, whereas infection in mammals most often results in lifelong
asymptomatic persistence.

AVIAN POLYOMAVIRUSES OF BIRD

The avian polyomaviruses (APyVs) display a broader host range. Budgerigar fledgling disease
polyomavirus was the first APyV discovered and can cause a devastating disease of young
budgerigars, with mortality rates up to 100%. The disease may be limited to feather dysplasia
of primary wing feathers and tail feathers, evident as absence of feathers or thick sheaths. In
young chicks, the disease may be systemic, with the virus usually forming lightly basophilic
intranuclear inclusions in the epithelial cells of the kidney, liver, and ventricles of the brain.
Necrosis of the liver is common, as is ascites and hydropericardium. If the fledglings survive,
they can develop chronic feather disorders as they age. Although the virus was at first
designated beak and feather disease polyomavirus, the currently accepted name of APyV
reflects the broad host range of the virus.

Although many bird species are susceptible, the degree of susceptibility, the tissue tropism, and
the resulting disease appears to be dependent on the species infected. For example, in larger
psittacine birds (parrots) the virus targets mononuclear phagocytic cells with inclusions being
most apparent, and sometimes exclusively, in the spleen, whereas in passerines APyV targets
endothelial cells.

Goose hemorrhagic polyomavirus (GHPyV) can cause acute and chronic inflammatory disease.
GHPyV is the causative agent of hemorrhagic nephritis and enteritis of young (2–10-week old)
geese. Characteristic lesions of nephritis, depletion of lymphocytes in the cloacal bursa,
enteritis, ascites, and edema of the subcutaneous tissues reflect an epithelial and endothelial
cell tropism of the virus.

Finch polyomavirus (FPyV), crow polyomavirus (CPyV), and canary polyomavirus (CaPyV) were
each isolated from diseased birds, however the clinical importance of these viruses has not
been well characterized

POLYOMAVIRUSES OF LABORATORY ANIMAL

a. Murine polyomavirus (MPyV) - the first polyomavirus discovered
b. SV40 can also cause natural disease, almost exclusively in immunosuppressed primates,
typically simian immunodeficiency virus infected rhesus macaques (Macaca mulatta). In
these animals, SV40 can cause progressive multifocal leukoencephalopathy. This
provided a valuable model to investigate the role of a human polyomavirus, JC virus, in
the development of progressive multifocal leukoencephalopathy in immunosuppressed
humans, such as those with acquired immunodeficiency syndrome (AIDS).
c. “Murine pneumotropic virus” (MPtV) – formerly known as K virus; mouse is the host.
Infection of immunodeficient neonates with this virus can result in pulmonary edema
and hemorrhage as a result of its tropism for, and cytolytic replication in, vascular
epithelium. Like other polyomaviruses, MPtV replicates in the kidney and is chronically
shed in urine. MPtV is nononcogenic compared to MPyV, since its genome lacks a
sequence for middle T (MT) antigen; MT antigen is the major transforming protein that
activates protein kinases of the c-Src family, and is used in many transgenic constructs
for induction of tumors in genetically engineered mice.
d. Syrian (Mesocricetus auratus) and European (Cricetus cricetus) hamsters can be infected
by a hamster polyomavirus. Like other mammalian polyomaviruses, hamster
polyomavirus infection of an immunodeficient animal can result in tumor formation.
Syrian hamsters have an undefined cellular immune deficiency that is likely due to their
highly inbred nature that renders them susceptible to hamster polyomavirus infection
and induction of tumors by polyomaviruses of other host species. When initially
introduced to a naive population of hamsters, hamster polyomavirus will induce massive
epizootics of transmissible lymphomas in young hamsters, generally arising initially in
the mesenteric lymph nodes, but involving several organs. When infection becomes
enzootic within the population, the prevalence of lymphomas decreases, and animals
often manifest multiple cutaneous epitheliomas. The natural host for hamster
polyomavirus is believed to be the European hamster, which does not develop disease.

OTHER MAMMALIAN POLYOMAVIRUSES

RacPyV has recently been discovered to be the likely cause of neuroglial brain tumors in free-
ranging raccoons (Procyon lotor) in the western United States. Evidence that the raccoon virus
causes these neoplasms includes the consistent detection of polyomaviruses in the tumors and
the detection of early gene expression in 60-80% of the tumor cells, but not adjacent normal
brain parenchyma. Additionally, RacPyV DNA can be detected in metastatic foci and tumor
tissue has a high load of virus. Persistent and innocuous infection by RacPyV can be detected
within multiple epithelial tissues, including epithelial cells of the kidney, in most raccoons.

Bovine polyomavirus is frequently present in bovine sera, especially fetal and neonatal calf sera.
However, no disease has been associated with infection, and the significance remains uncertain.
Similarly, a variety of polyomaviruses have been detected in free-living bats but their clinical
significance, if any, is currently unknown.
BANDICOOT PAPILLOMATOSIS CARCINOMATOSIS VIRUS

Bandicoot papillomatosis carcinomatosis virus (BPCV)- 1 and -2

 The first BPCV to be identified was detected in a series of papillomas and carcinomas of
the skin and mucocutaneous junctions of the endangered western barred bandicoot
(Perameles bougainville).
 BPCV-2 was identified in multiple papillomatous skin lesions on a southern brown
bandicoot (Isoodon obesulus)