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Sheep retrovirus structural protein induces lung tumours

Nature volume 434, pages 904–907 (2005)Cite this article

Abstract

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.

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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.

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Acknowledgements

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.

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  1. Sarah K. Wootton and Christine L. Halbert: These authors contributed equally to this work

Authors and Affiliations

  1. Fred Hutchinson Cancer Research Center, 1100 Fairview Avenue North, Seattle, Washington, 98109, USA

    Sarah K. Wootton, Christine L. Halbert & A. Dusty Miller

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  1. Sarah K. Wootton
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Correspondence to A. Dusty Miller.

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Wootton, S., Halbert, C. & Miller, A. Sheep retrovirus structural protein induces lung tumours. Nature 434, 904–907 (2005). https://doi.org/10.1038/nature03492

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