Animal papillomaviruses

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Structure:

small double stranded DNA viruses

non-enveloped (no lipid layer)

Caspid (L1 and L2 proteins) - protein layer on surface

Characteristic shape - star shaped structures on the surface (capsomeres)

*Icosohedral virus structure is most commonly seen in mammalian viruses (identical sub units)

Papillomaviruses infect a wide range of species :

can be asymptomatic (no lesions)

benign lesions can go onto form malignant lesions

infect epithelial cells, mucosal and cutaneous membranes

Type of virus can cause different lesions of different areas of the body = species specific

BPV1 + 2 = most common bovine PV found in cows - can cause bladder cancers and can also cause tumours in horses

*some papillomaviruses are cancer causing

HPV - Human Papillomaviruses

most cause warts (benign lesions)

a subset infect the anogenital region

most prevalent agent causing STDs after Chlamydia

some will infect mucosal membranes - cause carcinomas

*over 99% of cervical cancers are associated with HPV

Papillomavirus genome encodes 8 genes:

- E5, E6 and E7 are oncogenes

circular genome encodes number of early genes (E) and late genes (L)

E expressed early in life cycle

L expressed late in life cycle

Entry:

Attachment phase = virus binds to cell surface receptor (possible transferred to second receptor)

Internalisation = form of endocytosis (membrane re models/invaginates and forms close shell outside the virus and brings the virus into the cell

*P replicated mainly in the basal cells (keratinocytes) of the body surface tissues - won't replicate in the epidermal cells

Form benign lesions and often these will regress (6-12 months) - natural regression of immune system response with infection being cleared

*virus must be able to infect the basal cells as these are the only dividing cells of the skin or mucosal membrane - early genes are activated and expressed (oncogenes E5,6+7), virus replicates alongside the cells, all new cells will carry the viral genome

Late genes makes caspid proteins which are only formed in the very surface cell layers (virus can then shed off the surface of the skin)

*very unique timing of when genes get turned on and off - very unique to PV, showing link to the epidermal life cycle

Lifecycle:

• The PV genome consists of 8 genes; E1, E2, E4, E5, E6, E7, L1 + L2

• Early (E) genes are expressed early or late (L) in the life cycle of the virus

• HPV enters the nucleus of a basal epithelial cell, where early genes E1 and E2 are expressed, replicating the viral genome and transcribing messenger RNA needed for viral replication.

• As the host cells differentiate, E4 and E5 assist in the production of the viral genome

•E5, E6 and E7 are viral oncogenes

•Late genes L1 and L2 code for structural capsid proteins which encapsidate the viral genome.

E6 Oncoprotein:

in some PVs can degrade p53 (key tumour suppressor)

one of the most important 'brakes' on cancer development

p53 puts the brakes on cell growth via cell cycle arrest and apoptosis/cell death

E6 is an oncoprotein which can knock out p53 function by degrading it (in some HPV strains)

if p53 is degraded = genomic instability

E6 activated telomerase overcomes senescence and allows cell to be immortal

caps on chromosomes - usually telomeres get shorter over period of time and will stop dividing (cells overexpressing telomerase inside lose control of senescence and will continue to divide)

*telomerase immortalisation and loss of p53 function

E7 Oncogene:

can inactivate the retinoblastoma pRB protein

pRb prevents G1/S phase progression - critical control of cell proliferation

normally pRb becomes phosphorylated by the action of cyclin or cyclin dependent kinases

Hyperphosphorylated state - E2 dissociates and triggers cell out of G1 into the S phase

E7 can knock out pRb function - E2F signal is always on

E2 will tell cell to keep dividing, uncontrolled cell division

*Inhibits Rb giving constitutive E2F function

E1 and E2 proteins:

E1 - unwinds the double stranded DNA = needs energy to do this

E2 - replication, transcription and segregation of viral genome, tether the viral genome to host chromosomes, clever function allows for passage onto daughter cells and for spread of virus

More L1 capsid protein than L2 - provide a shell for the genome

*HPV DNA must become integrated into the host chromosome in order to cause malignant tumours (if not integrated - benign lesions)

Viral genome breaks and becomes integrated into host genome - deregulation and leads to invasive cancer - results in loss of E2 resulting in the increase of oncogene expression

*Xrays/UV rays, DNA damaging agents + toxic chemicals = cause breakage of genome

Bovine Papillomaviruses (BPV):

highly prevalent (50% cattle infected)

most skin warts rarely cause problems (only in show animals)

genital papillomas can cause problems with calving + milking if on teats

papillomas contain large amounts of infectious virus

transmission between animals is common - contamination of equipment or environment

lesions are left alone unless impacting welfare of the animals

*virus has to get into basal cells - skin acts as effective barrier usually, injury or micro abrasions to skin or previous site of injury - area where infection is most likely to occur

BPV - 4 is the causative agent on alimentary cattle Squamous cell carcinomas

BPV-1/2 is the causative agent of cattle bladder cancers

Bracken Fern is the cofactor for BPV induced oncogenesis in cattle- many BPV require co factors to act as another trigger

*bracken fern long term consumption acts as an immunosuppressant (and contains mutagens) resulting in animal unable to clear BPV infection low levels of long-term consumption acts as a cancer cofactor

Vaccines:

Gardasil - targets 4 different types

Cervavix - targets 2 of the most common

New one - targets a wider range of different viruses

Equine Sarcoid Tumours:

most common tumour in all equids

mainly caused by BPV-1

caused by BPV - cross species infection

skin tumours - affecting horses, donkeys and zebras

very difficult to treat

if cut them off they tend to come back, and come back worse

*now numerous reports of PV infections in their non natural species = cross-species infections (could be unique to BPV 1+2)