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Tumor viruses of animals
Ab Osterhaus
Department of Virology
• veterinary importance?
• lessons for human cancer?
• zoonotic potential?
History of tumor virology (1/2) Javier et al, RT Cancer Res. 2008
History of tumor virology (1/2) Javier et al, RT Cancer Res. 2008
Ciuffo
Ellerman and Bang
Peyton Rous: discovered avian virus
that induced tumors in chickens(1911)
Photo:The Rockefeller University Archives. Javier et al, RT Cancer Res. 2008
History of tumor virology (1/2) Javier et al, RT Cancer Res. 2008
Bittner
Shope
Gross
Animal tumor viruses as models
Javier et al, RT Cancer Res. 2008
Molecular epidemiology of
gibbon hepatitis B virus transmissionSuwanna Noppornpanth et al 2003
Fig. 1. Phylogram based on nucleotide
sequences of the complete S gene using the
Kimura two-parameter matrix and neighbour-
joining method. Bootstrap values (1000 total)
of 70 % are indicated on the branches.
Human and nonhuman primate HBV were
compared to gibbon and human HBV
isolates identified in this study.
Animal tumor viruses:
of veterinary importance (Truyen and Loechelt, 2006)
MMTV vs HMTV
MMTV causes breast cancer in mice (Bittner, 1936)
HMTV / Pogo virus associated with human breast cancer?
~ 660-bp env sequence similar to MMTV in breast cancers
~ env and LTR HMTV insertions in chromosomes (~MMTV)
~ HMTV in primary breast cancer cells
~ …
Retroviruses and tumors: poultry
Avian leukosis/sarcoma (L/S) group caused by α-retroviruses
tumor related mortality (acute or slow)
reduction egg production
subclinical immunosuppression
Endogenous versus exogenous ALVs
Acute transforming ALVs carry viral oncogenes
Slowly transforming ALVs insert LTR: activation of cellular oncogens
Retroviruses and tumors:
sheep and goats
Jaagsiekte caused by a β-retrovirus:
transmissible ovine pulmonary adenocarcinoma
tumor induction by respiratory tropic JSRVs Env protein
transformation upon binding hyaluronidase-2 receptor
aerosol transmission to suckling lambs
incubation time about 9 months
lung neoplasia (type 2 pneumocytes:
ovine pulmonary adenocarcinoma)
full blown disease after 1-3 years
enJSRVs Env supposed to play a key role in placentation
Involvement of enJSRV Env and Hyal-2 in placentationVarela et al, Ann N Y Acad Sci. 2009
mononuclear trophoblast cell
giant binuclear cell
endometrial luminal cell
cotyledone formation
Varela et al, Ann N Y Acad Sci. 2009
Retroviruses and tumors: cats
Feline leukemia virus: a γ-retrovirus
worldwide distribution (1-10%)
disease manifestations:
lymphosarcoma, “AIDS” / anaemia …
replication-defective viruses (feline
sarcoma viruses) carrying oncogenes
harbour oncogenic potential
horizontal and vertical transmission
natural and vaccine induced immunity
elimination and vaccination strategies
successful
Primate and feline lentiviruses
Yamamoto et al, Cell Science 2006
Retroviruses and tumors: cattle
Bovine leukosis virus: a δ-retrovirus
worldwide distribution (up to 100%)
transmission by infected lymphocytes (and vertical)
30% develop lymphocytosis and 5% tumors
persistent lymphocytosis: increased cell proliferation
eradication by screening programs
Phylogenetic analysis of 519 bp of LTR region sequenced from 81 strains of HTLV-I/STLV-I
Slattery J P et al. Genome Res. 1999;9:525-540
©1999 by Cold Spring Harbor Laboratory Press
Polyomaviruses in animals and humans
Mouse polyoma virus: tumors in susceptible mouse strains
SV40: rhesus monkeys
persistent infection in kidneys
` polio vaccination associated tumors
(rhesus versus cynomolgous kidneys)?
Human BKV: persistent infection in kidneys
nephropathy (immune-compromised)
tumors in experimentally infected mice
prostate cancer?
Human JCV: progressive multifocal leukoencephalopathy
(PML: in the immune- compromised)
tumors in experimentally infected mice
Human KI and WU viruses???
Mammalian papillomaviruses: Cattle
Six BPV types:
BPV 1 cutaneous fibropapilloma
BPV 2 cutaneous fibropapilloma
BPV 3 cutaneous fibropapilloma
BPV 4 intestinal tract papilloma
BPV 5 teat fibropailloma
BPV 6 teat papilloma
Bracken fern major co-factor for invasive
carcinomas alimentary tract (BPV 4) and
bladder (BPV 2)
BPV 1and 2 also in horses
M.S. Campo / Virus Research 89 (2002)
Bovine papillomaviruses: their role in the aetiology of cutaneous tumours of bovids and equids.
Nasir L, Campo MS. Vet Dermatol. 2008 Oct;19(5):243-54.
Bovine papillomavirus (BPV-4) lesions in the alimentary tractM.S. Campo / Virus Research 89 (2002)
M.S. Campo / Virus Research 89 (2002)
M.S. Campo / Virus Research 89 (2002)
Animal papillomaviruses: Horses
EPV causes benign warts
BPV 1 and 2 cause equine sarcoid
invasive fibrosarcoma-like processes
no metastasis
constant expression of E5
M.S. Campo / Virus Research 89 (2002)
Papillomaviruses: dogs
COPV 1 and 2: benign warts (skin, mouth, genital, conjunctiva)
More than 25% of dogs may be affected in kennels
Experimental vaccines work (whole virus, VLP, L1, E1, E2 and E7)
probably on the basis of a specific T cell reponse
M.S. Campo / Virus Research 89 (2002)
Herpesvirus evolutionary tree
Fish & Amphibian Mammalian & Avian Invertebrate
Herpesviruses’ Success:
Co-evolution of Virus and Host
Marek’s Disease: Gallid herpesvirus 2K.W.Jaronski et al.,Exp. Rev. Vaccines 2006
•alpha herpesvirus
•increasingly virulent strains last decades
•in face of comprehensive vaccination
•neurological symptoms
•chronic wasting
•multiple lymphomas:
•solid tumors in viscera and musculature
•MD-induced oncogenesis: many GHV-2 genes
Gallid Herpesvirus 2: Oncogenesis
K.W.Jaronski et al.,Exp. Rev. Vaccines 2006
Retroperitoneal Fibromatosis Herpesvirus Pathology
Retroperitoneal fibroma Bundels and fascicles, no vessels
Anti HHV8 LANA MoAb
Russel et al The Vet.J.,2009
Rhesus Rhadinovirus Pathology
Lymphocyte hyperplasia Vascular hyperplasia Follicular hyperplasia
Follicular dissolution Proliferative and hyalinized vessels
(~multicentric Castleman disease)
Russel et al The Vet.J.,2009
Malignant Catarrhal Fever: Ovine Herpesvirus 2
inapparent infection in natural host!
accumulation of CD8+ T cells in organs of other ungulates
CLOSE
Seal gammaherpesvirus
in immunocompromised mice Martina et al 2007
Myoepitheliomas (arrow head) in salivary gland
of a mouse treated with cyclosporin A and
infected with phocid herpesvirus type 2
The neoplasm consists of interlacing bundles of
spindle cells with marked anisokaryosis and
a variable number of mitoses (arrowhead).
Seal gammaherpesvirus
in immunocompromised African green monkeys Martina et al 2007
Follicular hyperplasia in the spleen of an African green monkey
treated with cyclosporin A and infected with phocid herpesvirus
type 2
The germinal centres (arrowheads) are markedly expanded and
retain a peripheral mantle zone.
Germinal centre, showing numerous mitoses (arrowheads) and
variation in cell type.
CONCLUSIONS
Importance of animal tumor viruses:
Veterinary: original pathogens for animals
~ wildlife
~ husbandry
~ companion animals
Animal models: studies of pathogenesis
and intervention strategies
Zoonoses: human or public health, heterologous species?
(examples in Herpes-, Papova-, and Retroviridae)
Emerging
virus infections
Department of Virology