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. 2005 Apr 14;434(7035):904-7.
doi: 10.1038/nature03492.

Sheep retrovirus structural protein induces lung tumours

Sarah K Wootton  1 , Christine L Halbert, A Dusty Miller
Affiliations

Sheep retrovirus structural protein induces lung tumours

Sarah K Wootton et al. Nature. .

Abstract

Jaagsiekte sheep retrovirus (JSRV) causes a contagious lung cancer in sheep and goats, with significant animal health and economic consequences. 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 humans. Sheep are immunotolerant of JSRV because of the expression of closely related endogenous retroviruses, 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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Figures

Figure 1
Figure 1
Scale drawings of the JSRV genome and the AAV vectors encoding JSRV Env (ARJenv) and AP (ARAP4). The JSRV-coding regions are staggered vertically to indicate the three different reading frames that encode the proteins. Gag, core polyprotein; kb, kilobase; LTR, retroviral long terminal repeat; Orf-X, open reading frame of unknown function; Pol, polymerase; Poly(A) signal, polyadenylation signal; Pro, protease and dUTPase; RSV, Rous sarcoma virus; TR, AAV terminal repeat.
Figure 2
Figure 2
Characteristics of lung tumours induced by JSRV Env in mice. a, Lung tumours (arrows) 2 months after vector exposure. b, Lung tumours at 6 months. c, Papillary adenoma surrounded by normal peripheral lung tissue (compressed near tumour) at 2.5 months. d, Adenocarcinoma at 6 months. e, Surface tumour at 2 months. f, Multiple tumours at 6 months. g, Human lung peripheral adenocarcinoma. h, Lung tumour in a lamb 2 months after JSRV infection. i, SP-C immunostaining. Tumour and type II cells in alveoli are stained but nearby airway is not. j, CC10 immunostaining of the tumour shown in i. Tumour is not stained but Clara cells lining the nearby airway are. k, JSRV Env immunostaining. l, Higher-magnification view of apical membrane Env staining. Arrows point to Env staining of apical membranes that face away from lung tissue and towards airways. Staining in c–h was with haematoxylin and eosin.
Figure 3
Figure 3
Env RNA expression in mouse lung and airways 4 months after the administration of ARJenv vector. RNA samples were subjected to reverse transcription and PCR amplification with primers flanking the intron in ARJenv (Fig. 1). The predicted product for spliced RNA is 597 base pairs (bp), whereas that for vector DNA is 1,065 bp. The 597-bp product was detected for all airway tissues of mice exposed to ARJenv vector and for Env-transformed NIH 3T3 mouse cells but was not detected for normal mouse lung. Amplification of residual vector DNA in RNA prepared from the cell line that was not treated with DNase or reverse transcriptase (—RT lane) showed the expected 1,065-bp vector DNA band.
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