Construction of a molecular clone of ovine enzootic nasal tumor virus

Jaagsiekte sheep retrovirus (JSRV) and enzootic nasal tumor virus (ENTV) are small-ruminant betaretroviruses that share high nucleotide and amino acid identity, utilize the same cellular receptor, hyaluronoglucosaminidase 2 (Hyal2) for entry, and transform tissues with their envelope (Env) glycoprotein; yet, they target discrete regions of the respiratory tract—the lung and nose, respectively. This distinct tissue selectivity makes them ideal tools with which to study the pathogenesis of betaretroviruses. To uncover the genetic determinants of tropism, we constructed JSRV–ENTV chimeric viruses and produced lentivectors pseudotyped with the Env proteins from JSRV (Jenv) and ENTV (Eenv). Through the transduction and infection of lung and nasal turbinate tissue slices, we observed that Hyal2 expression levels strongly influence ENTV entry, but that the long terminal repeat (LTR) promoters of these viruses are likely responsible for tissue-specificity. Furthermore, we show evidence of ENTV Env expression in chondrocytes within ENTV-infected nasal turbinate tissue, where Hyal2 is highly expressed. Our work suggests that the unique tissue tropism of JSRV and ENTV stems from the combined effort of the envelope glycoprotein-receptor interactions and the LTR and provides new insight into the pathogenesis of ENTV.

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Improved Enzootic Nasal Tumor Virus Pseudotype Packaging Cell Lines Reveal Virus Entry Requirements in Addition to the Primary Receptor Hyal2

Journal of Virology ◽

10.1128/jvi.79.1.87-94.2005 ◽

2005 ◽

Vol 79 (1) ◽

pp. 87-94 ◽

Cited By ~ 22

Author(s):

Neal S. Van Hoeven ◽

A. Dusty Miller

Keyword(s):

Cell Lines ◽

High Titer ◽

Surface Protein ◽

Retroviral Vectors ◽

Epithelial Cancers ◽

Wide Range ◽

Enzootic Nasal Tumor Virus ◽

Tumor Virus ◽

Nasal Tumor ◽

Env Protein

ABSTRACT Enzootic nasal tumor virus (ENTV) and jaagsiekte sheep retrovirus (JSRV) are closely related retroviruses that cause epithelial cancers of the respiratory tract in sheep and goats. Both viruses use the glycosylphosphatidylinositol (GPI)-anchored cell surface protein hyaluronidase 2 (Hyal2) as a receptor for cell entry, and entry is mediated by the envelope (Env) proteins encoded by these viruses. Retroviral vectors bearing JSRV Env can transduce cells from a wide range of species, with the exception of rodent cells. Because of the low titer of vectors bearing ENTV Env, it has been difficult to determine the tropism of ENTV vectors, which appeared to transduce cells from sheep and humans only. Here we have developed high-titer ENTV packaging cells and confirm that ENTV has a restricted host range compared to that of JSRV. Most cells that are not transduced by JSRV or ENTV vectors can be made susceptible following expression of human Hyal2 on the cells. However, five rat cell lines from different rat strains and different tissues that were engineered to express human Hyal2 were still only poorly infected by ENTV vectors, even though the ENTV Env protein could bind well to human Hyal2 expressed on four of these cell lines. These results indicate the possibility of a coreceptor requirement for these viruses.

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First case of nasal transitional carcinoma in a goat infected with Enzootic Nasal Tumor Virus in Belgium

Vlaams Diergeneeskundig Tijdschrift ◽

10.21825/vdt.v89i4.16995 ◽

2020 ◽

Vol 89 (4) ◽

pp. 226-230

Author(s):

A. Delaude ◽

E. Raes ◽

C. Leroux ◽

K. Chiers ◽

L. Sonck

Keyword(s):

Nasal Passage ◽

Neoplastic Tissue ◽

Computed Tomographic ◽

First Case ◽

Enzootic Nasal Tumor Virus ◽

Tumor Virus ◽

Nasal Tumor ◽

Retrobulbar Space ◽

Polymerase Chain ◽

The Right

An eleven-year-old, female goat was presented for evaluation of breathing difficulties and epistaxis. Radiographs and computed tomographic (CT) examination of the head revealed the presence of a space-occupying lesion involving the right nasal passage and invading the cranial vault and retrobulbar space. Histologic examination and detection of viral genome from the nasal mass led to the diagnosis of nasal transitional carcinoma with concomitant infection with Enzootic Nasal Tumor Virus (ENTV-2). In this case report, the presence of a nasal transitional carcinoma is described in a goat; a very rare tumor which, to the authors’ knowledge, has not been previously reported in goats. Reverse transcription polymerase chain reaction (RT-PCR) detected the genome of ENTV-2 within the neoplastic tissue, suggesting an infectious etiology.

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Development of real-time PCR-based methods for the detection of enzootic nasal tumor virus 2 in goats

Archives of Virology ◽

10.1007/s00705-018-04138-0 ◽

2019 ◽

Vol 164 (3) ◽

pp. 707-716 ◽

Cited By ~ 3

Author(s):

Evangelia D. Apostolidi ◽

Dimitra Psalla ◽

Taxiarchis Chassalevris ◽

Serafeim C. Chaintoutis ◽

Nektarios D. Giadinis ◽

...

Keyword(s):

Real Time ◽

Real Time Pcr ◽

Enzootic Nasal Tumor Virus ◽

Tumor Virus ◽

Nasal Tumor

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Envelope Proteins of Jaagsiekte Sheep Retrovirus and Enzootic Nasal Tumor Virus Induce Similar Bronchioalveolar Tumors in Lungs of Mice

Journal of Virology ◽

10.1128/jvi.00865-06 ◽

2006 ◽

Vol 80 (18) ◽

pp. 9322-9325 ◽

Cited By ~ 22

Author(s):

Sarah K. Wootton ◽

Christine L. Halbert ◽

A. Dusty Miller

Keyword(s):

Airway Epithelial Cells ◽

Tumor Formation ◽

Airway Epithelial ◽

Jaagsiekte Sheep Retrovirus ◽

Sheep And Goats ◽

Specific Tumor ◽

Enzootic Nasal Tumor Virus ◽

Tumor Virus ◽

Nasal Tumor ◽

Env Protein

ABSTRACT Jaagsiekte sheep retrovirus (JSRV) induces bronchioalveolar tumors in sheep and goats. Expression of the JSRV envelope (Env) protein in mouse airway epithelial cells induces similar tumors, indicating that Env expression is sufficient for tissue-specific tumor formation. Enzootic nasal tumor virus (ENTV) is related to JSRV but induces tumors in the nasal epithelium of sheep and goats. Here we found that ENTV Env can also induce tumors in mice but, unexpectedly, with a phenotype identical to that of tumors induced by the JSRV Env, indicating that factors other than Env mediate the tissue specificity of tumor induction by ENTV.

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Receptor Usage and Fetal Expression of Ovine Endogenous Betaretroviruses: Implications for Coevolution of Endogenous and Exogenous Retroviruses

Journal of Virology ◽

10.1128/jvi.77.1.749-753.2003 ◽

2003 ◽

Vol 77 (1) ◽

pp. 749-753 ◽

Cited By ~ 77

Author(s):

Thomas E. Spencer ◽

Manuela Mura ◽

C. Allison Gray ◽

Philip J. Griebel ◽

Massimo Palmarini

Keyword(s):

Lymphoid Cells ◽

Cellular Receptor ◽

Endogenous Viruses ◽

Fetal Lamb ◽

Enzootic Nasal Tumor Virus ◽

Tumor Virus ◽

Nasal Tumor ◽

Etiological Agents ◽

Hyaluronidase 2

ABSTRACT Betaretroviruses of sheep include two exogenous viruses, Jaagsiekte sheep retrovirus (JSRV) and enzootic nasal tumor virus (ENTV), and a group of endogenous viruses known as enJSRVs. The exogenous JSRV and ENTV are the etiological agents of ovine pulmonary adenocarcinoma (OPA) and enzootic nasal tumor (ENT), respectively. Sheep affected by OPA or ENT do not show an appreciable antibody response to JSRV or ENTV. Consequently, it is conceivable that enJSRV expression in the fetal lamb tolerizes sheep to the related exogenous viruses. In this study, possible mechanisms of interference between the sheep exogenous and endogenous betaretroviruses were investigated. In situ hybridization detected enJSRV RNAs in lymphoid cells associated with the lamina propria of the small intestine and in the thymus of sheep fetuses. Low-level expression of enJSRVs was also detected in the lungs. In addition, expression of enJSRVs was found to block entry of the exogenous JSRV, presumably via mechanisms of receptor interference. Indeed, enJSRVs, like JSRV and ENTV, were found to utilize hyaluronidase-2 as a cellular receptor.

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Bronchioloalveolar Carcinoma Not Related to Jaagsiekte Sheep Retrovirus in a Goat

Veterinary Pathology ◽

10.1354/vp.44-5-710 ◽

2007 ◽

Vol 44 (5) ◽

pp. 710-712 ◽

Cited By ~ 3

Author(s):

A. Ortin ◽

A. A. Benito ◽

D. Lacasta ◽

L. M. Ferrer ◽

M. De Las Heras

Keyword(s):

Lung Tumor ◽

Clinical Signs ◽

Bronchioloalveolar Carcinoma ◽

Alveolar Type ◽

Chain Reaction ◽

Jaagsiekte Sheep Retrovirus ◽

Enzootic Nasal Tumor Virus ◽

Tumor Virus ◽

Nasal Tumor ◽

Polymerase Chain

A spontaneous lung tumor in a 5–year-old goat of the Murciano-Granadina breed is described in this paper. Clinical signs of cachexia and tachypnoea were evident, and a considerable amount of white mucous foamy fluid was discharged from the nostrils when the animal's head was lowered. A lung tumor with the characteristics of bronchioloalveolar carcinoma was detected during histopathologic examination. The tumor cells were positive for surfactant proteins C and B, confirming that alveolar type II cells were the origin of the neoplasia. Tumor samples were tested by polymerase chain reaction, immunoblotting, and immunohistochemistry for the presence of Jaagsiekte sheep retrovirus (JSRV) and enzootic nasal tumor virus (ENTV), another retrovirus very closely related to JSRV, but all tests were negative. Therefore, this is the first reported case of spontaneous bronchioloalveolar carcinoma not related to JSRV or ENTV infection in a goat.

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A Novel Enzootic Nasal Tumor Virus Circulating in Goats from Southern China

Viruses ◽

10.3390/v11100956 ◽

2019 ◽

Vol 11 (10) ◽

pp. 956 ◽

Cited By ~ 1

Author(s):

Shao-Lun Zhai ◽

Dian-Hong Lv ◽

Zhi-Hong Xu ◽

Jie-Shi Yu ◽

Xiao-Hui Wen ◽

...

Keyword(s):

Southern China ◽

Guangdong Province ◽

Accession Number ◽

Base Pairs ◽

Goat Farm ◽

Enzootic Nasal Tumor Virus ◽

Nucleotide Insertion ◽

Tumor Virus ◽

Nasal Tumor ◽

Full Length Genome

Enzootic nasal tumor virus (ENTV) has two types, ENTV-1 in sheep and ENTV-2 in goats, respectively. In China, the incidence of ENTV-2 related diseases has increased year by year. In this study, we reported an outbreak of ENTV-2 in a commercial goat farm in Qingyuan city, Guangdong province, southern China. A full-length genome of ENTV-2 (designated GDQY2017), with 7479 base pairs, was sequenced. Although GDQY2017 shared the highest nucleotide identity with a Chinese ENTV-2 isolate (ENTV-2CHN4, GenBank accession number KU258873), it possesses distinct genome characteristics undescribed, including a non-continuous 21-nucleotide insertion in the gag gene and a non-continuous 12-nucleotide deletion in the env gene. Notably, most of these indel nucleotide sequences were originated from a Chinese jaagsiekte sheep retrovirus (JSRV) isolate (GenBank accession number DQ838494). In the gag and env genes, GDQY2017 was phylogenetically related to those Chinese ENTV-2 isolates and a Chinese JSRV isolate (DQ838494). For GDQY2017-like viruses, more surveillance work should be made to explain their pathogenicity in goat herds. To our knowledge, this study represents the first to demonstrate the circulating pattern of ENTV-2 in Guangdong province, China, which will help to better understand the epidemiology and genetic diversity of ENTV-2.

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Enzootic Nasal Tumor Virus Envelope Requires a Very Acidic pH for Fusion Activation and Infection

Journal of Virology ◽

10.1128/jvi.00648-08 ◽

2008 ◽

Vol 82 (18) ◽

pp. 9023-9034 ◽

Cited By ~ 21

Author(s):

Marceline Côté ◽

Thomas J. Kucharski ◽

Shan-Lu Liu

Keyword(s):

Low Ph ◽

Prolonged Treatment ◽

Close Relative ◽

Target Cells ◽

Acidic Ph ◽

Enzootic Nasal Tumor Virus ◽

Tumor Virus ◽

Nasal Tumor ◽

Ph Dependent ◽

Env Protein

ABSTRACT Enzootic nasal tumor virus (ENTV) is a close relative of jaagsiekte sheep retrovirus (JSRV), and the two viruses use the same receptor, hyaluronidase 2 (Hyal2), for cell entry. We report here that, unlike the JSRV envelope (Env) protein, the ENTV Env protein does not induce cell fusion at pHs of 5.0 and above but requires a much lower pH (4.0 to 4.5) for fusion to occur. The entry of ENTV Env pseudovirions was substantially inhibited by bafilomycin A1 (BafA1) but was surprisingly enhanced by lysosomotropic agents and lysosomal protease inhibitors following a 4- to 6-h treatment period; of note, prolonged treatment with BafA1 or ammonium chloride completely blocked ENTV entry. Unlike typical pH-dependent viruses, ENTV Env pseudovirions were virtually resistant to inactivation at a low pH (4.5 or 5.0). Using chimeras formed from ENTV and JSRV Env proteins, we demonstrated that the transmembrane (TM) subunit of ENTV Env is primarily responsible for its unusually low pH requirement for fusion but found that the surface (SU) subunit of ENTV Env also critically influences its relatively low and pH-dependent fusion activity. Furthermore, the poor infectivity of ENTV pseudovirions in human cells was significantly improved by either replacing the SU subunit of ENTV Env with that of JSRV Env or overexpressing the functional Hyal2 receptor in target cells, suggesting that ENTV SU-Hyal2 interaction is likely to be the limiting step for viral infectivity. Collectively, our data reveal that the fusogenicity of ENTV Env is intrinsically lower than that of JSRV Env and that ENTV requires a more acidic pH for fusion, which may occur in an intracellular compartment(s) distinct from that used by JSRV.

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