veterinary importance? lessons for human cancer? zoonotic ... · retroviruses and tumors: sheep and...

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