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Tumor viruses of animals Ab Osterhaus Department of Virology veterinary importance? lessons for human cancer? zoonotic potential?

veterinary importance? lessons for human cancer? zoonotic ... · Retroviruses and tumors: sheep and goats Jaagsiekte caused by a -retrovirus: transmissible ovine pulmonary adenocarcinoma

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Page 1: veterinary importance? lessons for human cancer? zoonotic ... · Retroviruses and tumors: sheep and goats Jaagsiekte caused by a -retrovirus: transmissible ovine pulmonary adenocarcinoma

Tumor viruses of animals

Ab Osterhaus

Department of Virology

• veterinary importance?

• lessons for human cancer?

• zoonotic potential?

Page 2: veterinary importance? lessons for human cancer? zoonotic ... · Retroviruses and tumors: sheep and goats Jaagsiekte caused by a -retrovirus: transmissible ovine pulmonary adenocarcinoma

History of tumor virology (1/2) Javier et al, RT Cancer Res. 2008

Page 3: veterinary importance? lessons for human cancer? zoonotic ... · Retroviruses and tumors: sheep and goats Jaagsiekte caused by a -retrovirus: transmissible ovine pulmonary adenocarcinoma

History of tumor virology (1/2) Javier et al, RT Cancer Res. 2008

Ciuffo

Ellerman and Bang

Page 4: veterinary importance? lessons for human cancer? zoonotic ... · Retroviruses and tumors: sheep and goats Jaagsiekte caused by a -retrovirus: transmissible ovine pulmonary adenocarcinoma

Peyton Rous: discovered avian virus

that induced tumors in chickens(1911)

Photo:The Rockefeller University Archives. Javier et al, RT Cancer Res. 2008

Page 5: veterinary importance? lessons for human cancer? zoonotic ... · Retroviruses and tumors: sheep and goats Jaagsiekte caused by a -retrovirus: transmissible ovine pulmonary adenocarcinoma

History of tumor virology (1/2) Javier et al, RT Cancer Res. 2008

Bittner

Shope

Gross

Page 6: veterinary importance? lessons for human cancer? zoonotic ... · Retroviruses and tumors: sheep and goats Jaagsiekte caused by a -retrovirus: transmissible ovine pulmonary adenocarcinoma

Animal tumor viruses as models

Javier et al, RT Cancer Res. 2008

Page 7: veterinary importance? lessons for human cancer? zoonotic ... · Retroviruses and tumors: sheep and goats Jaagsiekte caused by a -retrovirus: transmissible ovine pulmonary adenocarcinoma

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.

Page 8: veterinary importance? lessons for human cancer? zoonotic ... · Retroviruses and tumors: sheep and goats Jaagsiekte caused by a -retrovirus: transmissible ovine pulmonary adenocarcinoma

Animal tumor viruses:

of veterinary importance (Truyen and Loechelt, 2006)

Page 9: veterinary importance? lessons for human cancer? zoonotic ... · Retroviruses and tumors: sheep and goats Jaagsiekte caused by a -retrovirus: transmissible ovine pulmonary adenocarcinoma
Page 10: veterinary importance? lessons for human cancer? zoonotic ... · Retroviruses and tumors: sheep and goats Jaagsiekte caused by a -retrovirus: transmissible ovine pulmonary adenocarcinoma

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

~ …

Page 11: veterinary importance? lessons for human cancer? zoonotic ... · Retroviruses and tumors: sheep and goats Jaagsiekte caused by a -retrovirus: transmissible ovine pulmonary adenocarcinoma

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

Page 12: veterinary importance? lessons for human cancer? zoonotic ... · Retroviruses and tumors: sheep and goats Jaagsiekte caused by a -retrovirus: transmissible ovine pulmonary adenocarcinoma

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

Page 13: veterinary importance? lessons for human cancer? zoonotic ... · Retroviruses and tumors: sheep and goats Jaagsiekte caused by a -retrovirus: transmissible ovine pulmonary adenocarcinoma

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

Page 14: veterinary importance? lessons for human cancer? zoonotic ... · Retroviruses and tumors: sheep and goats Jaagsiekte caused by a -retrovirus: transmissible ovine pulmonary adenocarcinoma

Varela et al, Ann N Y Acad Sci. 2009

Page 15: veterinary importance? lessons for human cancer? zoonotic ... · Retroviruses and tumors: sheep and goats Jaagsiekte caused by a -retrovirus: transmissible ovine pulmonary adenocarcinoma

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

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Page 17: veterinary importance? lessons for human cancer? zoonotic ... · Retroviruses and tumors: sheep and goats Jaagsiekte caused by a -retrovirus: transmissible ovine pulmonary adenocarcinoma

Primate and feline lentiviruses

Yamamoto et al, Cell Science 2006

Page 18: veterinary importance? lessons for human cancer? zoonotic ... · Retroviruses and tumors: sheep and goats Jaagsiekte caused by a -retrovirus: transmissible ovine pulmonary adenocarcinoma

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

Page 19: veterinary importance? lessons for human cancer? zoonotic ... · Retroviruses and tumors: sheep and goats Jaagsiekte caused by a -retrovirus: transmissible ovine pulmonary adenocarcinoma

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

Page 20: veterinary importance? lessons for human cancer? zoonotic ... · Retroviruses and tumors: sheep and goats Jaagsiekte caused by a -retrovirus: transmissible ovine pulmonary adenocarcinoma

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???

Page 21: veterinary importance? lessons for human cancer? zoonotic ... · Retroviruses and tumors: sheep and goats Jaagsiekte caused by a -retrovirus: transmissible ovine pulmonary adenocarcinoma

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)

Page 22: veterinary importance? lessons for human cancer? zoonotic ... · Retroviruses and tumors: sheep and goats Jaagsiekte caused by a -retrovirus: transmissible ovine pulmonary adenocarcinoma

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.

Page 23: veterinary importance? lessons for human cancer? zoonotic ... · Retroviruses and tumors: sheep and goats Jaagsiekte caused by a -retrovirus: transmissible ovine pulmonary adenocarcinoma

Bovine papillomavirus (BPV-4) lesions in the alimentary tractM.S. Campo / Virus Research 89 (2002)

Page 24: veterinary importance? lessons for human cancer? zoonotic ... · Retroviruses and tumors: sheep and goats Jaagsiekte caused by a -retrovirus: transmissible ovine pulmonary adenocarcinoma

M.S. Campo / Virus Research 89 (2002)

Page 25: veterinary importance? lessons for human cancer? zoonotic ... · Retroviruses and tumors: sheep and goats Jaagsiekte caused by a -retrovirus: transmissible ovine pulmonary adenocarcinoma

M.S. Campo / Virus Research 89 (2002)

Page 26: veterinary importance? lessons for human cancer? zoonotic ... · Retroviruses and tumors: sheep and goats Jaagsiekte caused by a -retrovirus: transmissible ovine pulmonary adenocarcinoma

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)

Page 27: veterinary importance? lessons for human cancer? zoonotic ... · Retroviruses and tumors: sheep and goats Jaagsiekte caused by a -retrovirus: transmissible ovine pulmonary adenocarcinoma

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)

Page 28: veterinary importance? lessons for human cancer? zoonotic ... · Retroviruses and tumors: sheep and goats Jaagsiekte caused by a -retrovirus: transmissible ovine pulmonary adenocarcinoma

Herpesvirus evolutionary tree

Fish & Amphibian Mammalian & Avian Invertebrate

Page 29: veterinary importance? lessons for human cancer? zoonotic ... · Retroviruses and tumors: sheep and goats Jaagsiekte caused by a -retrovirus: transmissible ovine pulmonary adenocarcinoma

Herpesviruses’ Success:

Co-evolution of Virus and Host

Page 30: veterinary importance? lessons for human cancer? zoonotic ... · Retroviruses and tumors: sheep and goats Jaagsiekte caused by a -retrovirus: transmissible ovine pulmonary adenocarcinoma

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

Page 31: veterinary importance? lessons for human cancer? zoonotic ... · Retroviruses and tumors: sheep and goats Jaagsiekte caused by a -retrovirus: transmissible ovine pulmonary adenocarcinoma

Gallid Herpesvirus 2: Oncogenesis

K.W.Jaronski et al.,Exp. Rev. Vaccines 2006

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Retroperitoneal Fibromatosis Herpesvirus Pathology

Retroperitoneal fibroma Bundels and fascicles, no vessels

Anti HHV8 LANA MoAb

Russel et al The Vet.J.,2009

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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

Page 37: veterinary importance? lessons for human cancer? zoonotic ... · Retroviruses and tumors: sheep and goats Jaagsiekte caused by a -retrovirus: transmissible ovine pulmonary adenocarcinoma

Malignant Catarrhal Fever: Ovine Herpesvirus 2

inapparent infection in natural host!

accumulation of CD8+ T cells in organs of other ungulates

Page 38: veterinary importance? lessons for human cancer? zoonotic ... · Retroviruses and tumors: sheep and goats Jaagsiekte caused by a -retrovirus: transmissible ovine pulmonary adenocarcinoma

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).

Page 39: veterinary importance? lessons for human cancer? zoonotic ... · Retroviruses and tumors: sheep and goats Jaagsiekte caused by a -retrovirus: transmissible ovine pulmonary adenocarcinoma

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.

Page 40: veterinary importance? lessons for human cancer? zoonotic ... · Retroviruses and tumors: sheep and goats Jaagsiekte caused by a -retrovirus: transmissible ovine pulmonary adenocarcinoma

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)

Page 41: veterinary importance? lessons for human cancer? zoonotic ... · Retroviruses and tumors: sheep and goats Jaagsiekte caused by a -retrovirus: transmissible ovine pulmonary adenocarcinoma

Emerging

virus infections

Department of Virology