Skip to main content

Thank you for visiting You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Sheep retrovirus structural protein induces lung tumours


Jaagsiekte sheep retrovirus (JSRV) causes a contagious lung cancer in sheep and goats, with significant animal health and economic consequences1. The host range of JSRV is in part limited by species-specific differences in the virus entry receptor, hyaluronidase 2 (Hyal2), which is not functional as a receptor in mice but is functional in humans2. Sheep are immunotolerant of JSRV because of the expression of closely related endogenous retroviruses3,4, which are not present in humans and most other species, and this may facilitate oncogenesis. Here we show that expression of the JSRV envelope (Env) protein alone in lungs of mice, by using a replication-incompetent adeno-associated virus vector, results in tumours with a bronchiolo-alveolar localization like those seen in sheep. Whereas lethal disease was observed in immunodeficient mice, tumour development was almost entirely blocked in immunocompetent mice. Our results provide a rare example of an oncogenic viral structural protein, show that interaction of the viral Env protein with the virus entry receptor Hyal2 is not required for tumorigenesis, and indicate that immune recognition of Env can protect against JSRV tumorigenesis.

This is a preview of subscription content, access via your institution

Relevant articles

Open Access articles citing this article.

Access options

Rent or buy this article

Prices vary by article type



Prices may be subject to local taxes which are calculated during checkout

Figure 1: Scale drawings of the JSRV genome and the AAV vectors encoding JSRV Env (ARJenv) and AP (ARAP4).
Figure 2: Characteristics of lung tumours induced by JSRV Env in mice.
Figure 3: Env RNA expression in mouse lung and airways 4 months after the administration of ARJenv vector.


  1. Fan, H. (ed.) Jaagsiekte Sheep Retrovirus and Lung Cancer (Springer, Berlin, 2003)

  2. Rai, S. K. et al. Candidate tumor suppressor HYAL2 is a glycosylphosphatidylinositol (GPI)-anchored cell-surface receptor for jaagsiekte sheep retrovirus, the envelope protein of which mediates oncogenic transformation. Proc. Natl Acad. Sci. USA 98, 4443–4448 (2001)

    Article  ADS  CAS  Google Scholar 

  3. Spencer, T. E., Mura, M., Gray, C. A., Griebel, P. J. & Palmarini, M. Receptor usage and fetal expression of ovine endogenous betaretroviruses: implications for coevolution of endogenous and exogenous retroviruses. J. Virol. 77, 749–753 (2003)

    Article  CAS  Google Scholar 

  4. Summers, C. et al. Systemic immune responses following infection with Jaagsiekte sheep retrovirus and in the terminal stages of ovine pulmonary adenocarcinoma. J. Gen. Virol. 83, 1753–1757 (2002)

    Article  CAS  Google Scholar 

  5. Sharp, J. M., Angus, K. W., Gray, E. W. & Scott, F. M. Rapid transmission of sheep pulmonary adenomatosis (jaagsiekte) in young lambs. Brief report. Arch. Virol. 78, 89–95 (1983)

    Article  CAS  Google Scholar 

  6. Maeda, N., Palmarini, M., Murgia, C. & Fan, H. Direct transformation of rodent fibroblasts by jaagsiekte sheep retrovirus DNA. Proc. Natl Acad. Sci. USA 98, 4449–4454 (2001)

    Article  ADS  CAS  Google Scholar 

  7. Allen, T. E. et al. The jaagsiekte sheep retrovirus envelope gene induces transformation of the avian fibroblast cell line DF-1 but does not require a conserved SH2 binding domain. J. Gen. Virol. 83, 2733–2742 (2002)

    Article  CAS  Google Scholar 

  8. Liu, S.-L. & Miller, A. D. Transformation of Madin–Darby canine kidney (MDCK) epithelial cells by sheep retrovirus envelope proteins. J. Virol. 79, 927–933 (2004)

    Article  Google Scholar 

  9. Palmarini, M. et al. A phosphatidylinositol 3-kinase docking site in the cytoplasmic tail of the Jaagsiekte sheep retrovirus transmembrane protein is essential for envelope-induced transformation of NIH 3T3 cells. J. Virol. 75, 11002–11009 (2001)

    Article  CAS  Google Scholar 

  10. Liu, S.-L., Lerman, M. I. & Miller, A. D. Putative phosphatidylinositol 3-kinase (PI3K) binding motifs in ovine betaretrovirus Env proteins are not essential for rodent fibroblast transformation and PI3K/Akt activation. J. Virol. 77, 7924–7935 (2003)

    Article  CAS  Google Scholar 

  11. Danilkovitch-Miagkova, A. et al. Hyaluronidase 2 negatively regulates RON receptor tyrosine kinase and mediates transformation of epithelial cells by jaagsiekte sheep retrovirus. Proc. Natl Acad. Sci. USA 100, 4580–4585 (2003)

    Article  ADS  CAS  Google Scholar 

  12. Halbert, C. L., Allen, J. M. & Miller, A. D. Adeno-associated virus type 6 (AAV6) vectors mediate efficient transduction of airway epithelial cells in mouse lungs compared to that of AAV2 vectors. J. Virol. 75, 6615–6624 (2001)

    Article  CAS  Google Scholar 

  13. Allen, J. M., Halbert, C. L. & Miller, A. D. Improved adeno-associated virus vector production with transfection of a single helper adenovirus gene, E4orf6. Mol. Ther. 1, 88–95 (2000)

    Article  CAS  Google Scholar 

  14. Malkinson, A. M. The genetic basis of susceptibility to lung tumors in mice. Toxicology 54, 241–271 (1989)

    Article  CAS  Google Scholar 

  15. Platt, J. A., Kraipowich, N., Villafane, F. & DeMartini, J. C. Alveolar type II cells expressing jaagsiekte sheep retrovirus capsid protein and surfactant proteins are the predominant neoplastic cell type in ovine pulmonary adenocarcinoma. Vet. Pathol. 39, 341–352 (2002)

    Article  CAS  Google Scholar 

  16. Rai, S. K., DeMartini, J. C. & Miller, A. D. Retrovirus vectors bearing jaagsiekte sheep retrovirus Env transduce human cells by using a new receptor localized to chromosome 3p21.3. J. Virol. 74, 4698–4704 (2000)

    Article  CAS  Google Scholar 

  17. Liu, S.-L., Duh, F.-M., Lerman, M. I. & Miller, A. D. Role of virus receptor Hyal2 in oncogenic transformation of rodent fibroblasts by sheep betaretrovirus env proteins. J. Virol. 77, 2850–2858 (2003)

    Article  CAS  Google Scholar 

  18. Miller, A. D., Van Hoeven, N. S. & Liu, S.-L. Transformation and scattering activities of the receptor tyrosine kinase RON/Stk in rodent fibroblasts and lack of regulation by the jaagsiekte sheep retrovirus receptor, Hyal2. BMC Cancer 4, 64 (2004)

    Article  Google Scholar 

  19. Fisher, G. H. et al. Development of a flexible and specific gene delivery system for production of murine tumor models. Oncogene 18, 5253–5260 (1999)

    Article  CAS  Google Scholar 

  20. De las Heras, M. et al. Evidence for a protein related immunologically to the jaagsiekte sheep retrovirus in some human lung tumours. Eur. Respir. J. 16, 330–332 (2000)

    Article  CAS  Google Scholar 

  21. Yousem, S. A., Finkelstein, S. D., Swalsky, P. A., Bakker, A. & Ohori, N. P. Absence of jaagsiekte sheep retrovirus DNA and RNA in bronchioloalveolar and conventional human pulmonary adenocarcinoma by PCR and RT-PCR analysis. Hum. Pathol. 32, 1039–1042 (2001)

    Article  CAS  Google Scholar 

  22. Hiatt, K. M. & Highsmith, W. E. Lack of DNA evidence for jaagsiekte sheep retrovirus in human bronchioloalveolar carcinoma. Hum. Pathol. 33, 680 (2002)

    Article  CAS  Google Scholar 

  23. Halbert, C. L., Allen, J. M. & Miller, A. D. Efficient mouse airway transduction following recombination between AAV vectors carrying parts of a larger gene. Nature Biotechnol. 20, 697–701 (2002)

    Article  CAS  Google Scholar 

  24. Halbert, C. L. et al. Transduction by adeno-associated virus vectors in the rabbit airway: efficiency, persistence, and readministration. J. Virol. 71, 5932–5941 (1997)

    CAS  PubMed  PubMed Central  Google Scholar 

Download references


We thank J. C. DeMartini for providing histological pictures of human and sheep tumours shown in Fig. 2 and for discussions, and K. Hudkins-Loya and C. Alpers for help with the histological and antibody staining. This work was supported by NIH grants and a postdoctoral fellowship to S.K.W. from the National Sciences and Engineering Research Council of Canada.

Author information

Authors and Affiliations


Corresponding author

Correspondence to A. Dusty Miller.

Ethics declarations

Competing interests

The authors declare that they have no competing financial interests.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Wootton, S., Halbert, C. & Miller, A. Sheep retrovirus structural protein induces lung tumours. Nature 434, 904–907 (2005).

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI:

This article is cited by


By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.


Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing