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Journal of Virology, June 2002, p. 5387-5394, Vol. 76, No. 11
0022-538X/02/$04.00+0     DOI: 10.1128/JVI.76.11.5387-5394.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Envelope-Induced Cell Transformation by Ovine Betaretroviruses

Alberto Alberti,1,2 Claudio Murgia,1 Shan-Lu Liu,3,4 Manuela Mura,1,5 Chris Cousens,6 Mike Sharp,6 A. Dusty Miller,3,4 and Massimo Palmarini1*

Department of Medical Microbiology and Parasitology, College of Veterinary Medicine, University of Georgia, Athens, Georgia 30602,1 Istituto di Patologia Speciale e Clinica Medica Veterinaria,2 Istituto di Patologia Generale, Anatomia Patologica e Clinica Ostetrico-Chirurgica Veterinaria, Facoltà di Medicina Veterinaria, Università degli Studi di Sassari, 07100 Sassari, Italy,5 Division of Human Biology, Fred Hutchinson Cancer Research Center, Seattle, Washington 98109-1024,3 Department of Pathology, University of Washington, Seattle, Washington 98195,4 Moredun Research Institute, International Research Center, Penicuik, Midlothian EH26 0PZ, United Kingdom6

Received 19 December 2001/ Accepted 21 February 2002

Ovine betaretroviruses include Jaagsiekte sheep retrovirus (JSRV) and enzootic nasal tumor virus (ENTV). JSRV and ENTV represent a unique class of oncogenic retroviruses that induce tumors of the respiratory tract. JSRV and ENTV are highly related but induce different diseases. Expression of the JSRV envelope (Env) induces transformation of rodent fibroblasts in vitro and phosphorylation of Akt, a central player in the phosphatidylinositol 3-kinase (PI-3K)/Akt signal transduction pathway. However, little information is available on the molecular biology of ENTV. In this study, we initially assessed whether the ENTV Env has the same properties as the homologous JSRV protein. We performed entry and interference assays using retroviral vectors pseudotyped with either the JSRV or the ENTV Env and sheep choroid plexus cells, choroid plexus cells stably expressing the JSRV Env protein, human 293T cells, mouse NIH 3T3 cells, or NIH 3T3 cells expressing human hyaluronidase 2 (HYAL2), the cellular receptor for JSRV. The results obtained indicated that ENTV and JSRV share the same receptor in sheep cells and that they can use human HYAL2 as a cellular receptor in mouse cells. The ENTV Env induces transformation of rodent fibroblasts in vitro. As with the JSRV Env, the tyrosine at position 590 is critical for ENTV Env-induced cell transformation, and Akt is phosphorylated in ENTV Env-transformed cells but not in the parental cell lines. Thus, ovine betaretroviruses share a common mechanism of cell transformation. We further investigated the relevance of Akt activation in cells transformed by ovine betaretroviruses. A PI-3K inhibitor blocked Akt phosphorylation in JSRV Env-transformed cells, suggesting a possible involvement of PI-3K in JSRV and ENTV Env-induced cell transformation. In addition, phosphorylated Akt was detected in a cell line derived from a lung tumor of a sheep with naturally occurring ovine pulmonary adenocarcinoma.

* Corresponding author. Mailing address: Department of Medical Microbiology and Parasitology, College of Veterinary Medicine, University of Georgia, Athens, GA 30607. Phone: (706) 542-4784. Fax: (706) 542-5771. E-mail: mpalmari{at}vet.uga.edu.

Journal of Virology, June 2002, p. 5387-5394, Vol. 76, No. 11
0022-538X/02/$04.00+0     DOI: 10.1128/JVI.76.11.5387-5394.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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