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Hung Fan - One of the best experts on this subject based on the ideXlab platform.
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role for a zinc finger protein zfp111 in transformation of 208f rat fibroblasts by Jaagsiekte Sheep Retrovirus envelope protein
Journal of Virology, 2015Co-Authors: Tom Hsu, An Phung, Kevin Choe, Jung Woo Kim, Hung FanAbstract:ABSTRACT The native envelope gene ( env ) of Jaagsiekte Sheep Retrovirus (JSRV) also acts as an oncogene. To investigate the mechanism of transformation, we performed yeast 2-hybrid screening for cellular proteins that interact with Env. Among several candidates, we identified mouse or rat zinc finger protein 111 ( zfp111 ). The interaction between Env and Zfp111 was confirmed through in vivo coimmunoprecipitation assays. Knockdown of endogenous Zfp111 caused a decrease in cell transformation by JSRV Env, while overexpression of Zfp111 increased overall Env transformation, supporting a role for Zfp111 in Env transformation. Knockdown of Zfp111 had no effect on the growth rate of parental rat 208F cells, while it decreased the proliferation rate of JSRV-transformed 208F cells, suggesting that JSRV-transformed cells became dependent on Zfp111. In addition, Zfp111 preferentially bound to a higher-mobility form of JSRV Env that has not been described previously. The higher-mobility form of Env (P70 env ) was found exclusively in the nuclear fraction, and size of its polypeptide backbone was the same as that of the cytoplasmic Env polyprotein (Pr80 env ). The differences in glycosylation between the two versions of Env were characterized. These results identify a novel cellular protein, Zfp111, that binds to the JSRV Env protein, and this binding plays a role in Env transformation. These results indicate that JSRV transformation also involves proteins and interactions in the nucleus. IMPORTANCE The envelope protein (Env) of Jaagsiekte Sheep Retrovirus (JSRV) is an oncogene, but its mechanism of cell transformation is still unclear. Here we identified seven candidate cellular proteins that can interact with JSRV Env by yeast two-hybrid screening. This study focused on one of the seven candidates, zinc finger protein 111 (Zfp111). Zfp111 was shown to interact with JSRV Env in cells and to be involved in JSRV transformation. Moreover, coexpression of JSRV Env and Zfp111 led to the identification of a novel nuclear form of the JSRV Env protein that binds Zfp111. Nuclear Env was found to differ by glycosylation from the cytoplasmic Env precursor to the virion envelope proteins. These results suggest that JSRV Env transformation may involve nuclear events such as an alteration in transcription mediated by Env-Zfp111 interactions.
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Analysis of Jaagsiekte Sheep Retrovirus (JSRV) envelope protein domains in transformation
Virus Genes, 2012Co-Authors: Stacey Hull, Joohyun Lim, Alexander Hamil, Takayuki Nitta, Hung FanAbstract:Jaagsiekte Sheep Retrovirus (JSRV) is the causative agent of a transmissible lung cancer in Sheep. A unique feature is that JSRV envelope protein is also the oncogene for this virus. Previous studies have identified the cytoplasmic tail (CT) of the envelope transmembrane (TM) protein as critical for transformation although other regions of Env have also been implicated. In this study, the roles of other Env regions in transformation were investigated. Chimeras between JSRV Env and the Env of a related non-oncogenic endogenous Retrovirus (enJSRV, 5F16) were used. A chimera containing the membrane-spanning region (MSR) of enJSRV inserted into JSRV Env showed substantially reduced transformation, indicating that the MSR plays a role in transformation. Transformation by this chimera was highly dependent on both Ras/Raf/MEK/MAPK and PI3K/Akt/mTOR signaling. A chimera containing the two amino acids in the TM ectodomain that distinguish JSRV and enJSRV showed modestly reduced transformation. Chimeras in the SU protein indicated that the amino terminal region of SU contributes to transformation, while the C-terminal part is not important. To test if Env trimerization is important for transformation, we mutated a leucine-rich sequence in the putative trimerization domain in the ectodomain of TM (Tri-M). This mutant could not transform cells and it did not oligomerize. However, Tri-M could complement a non-transforming mutant CT mutant (Y590F) so oligomerization is not necessary for at least some aspects of transformation. These experiments provide new insight into the regions and residues of JSRV Env protein necessary for oncogenic transformation.
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the oncogenic Jaagsiekte Sheep Retrovirus cytoplasmic tail adopts a unique conformation on a phosphocholine surface
Biophysical Journal, 2012Co-Authors: Ali Alhoshani, Hung Fan, Naoyoshi Maeda, Jessica Schulz, Saskia Milton, Charles G Glabe, Melanie J CoccoAbstract:Jaagsiekte Sheep Retrovirus (JSRV) is the etiologic agent of a transmissible lung cancer in Sheep, ovine pulmonary adenocarcinoma (OPA). OPA resembles bronchiole-alveolar carcinoma in humans, and it is an excellent animal model for this disease. A unique feature of JSRV is that the viral envelope (Env) protein also functions as an oncogene, in that expression JSRV Env protein causes morphological transformation of fibroblast and epithelial cell lines, and vectored Env expression induces epithelial tumors in several animals. Previous studies showed that the region containing the short 46 amino acid C-terminal cytoplasmic tail (CT) of JSRV Env is essential for the ability of JSRV to transform cells. Residues in the cytoplasmic tail include a tyrosine (Y590), which is present in a consensus motif YXXM, which could potentially bind the regulatory subunit of phosphatidyl inositol 3-kinase (PI3K) if the Y590 is phosphorylated. Alanine scanning mutagenesis on the JSRV TM cytoplasmic tail has been conducted. Mutation of some residues abolished Env transformation potential, while mutation of other residues had not effect or partial effects. To further understand the mechanism of JSRV transformation, structure-function analysis of the TM cytoplasm tail (CT) is important. We have determined the structure of the JSRV CT using NMR spectroscopy. These data allow us to interpret the alanine scanning mutagenesis, and allow better understanding of previous studies. Interestingly, using both CD and NMR, we find that the CT is only structured in the presence of a phosphocholine surface. The results validated some aspects of the predicted structure, and they also provided a basis for evaluating models of transformation.This work was funded by NIH CA94188
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three dimensional culture of an ovine pulmonary adenocarcinoma derived cell line results in re expression of surfactant proteins and Jaagsiekte Sheep Retrovirus
Virology, 2011Co-Authors: Chassidy Johnson, Hung FanAbstract:Jaagsiekte Sheep Retrovirus (JSRV) is the causative agent of ovine pulmonary adenocarcinoma (OPA) in Sheep. A major interest is elucidating the mechanism(s) of transformation by the viral envelope (Env) that functions as an oncogene. These studies would benefit from a cell line derived from type II pneumocytes that have maintained the differentiation state. In this study we used an OPA-derived cell line (JS7), which has lost structural and functional properties of type II pneumocytes, and no longer expresses JSRV when grown in 2-D monolayer culture. When JS7 cells were placed in 3-D culture using Matrigel, they grew as small spheres of polarized cells that re-expressed surfactant proteins characteristic of type II pneumocytes. Moreover, JS7 cells grown in 3-D re-expressed JSRV virus by several criteria. This study underscores the importance of the culture environment on maintaining the differentiation state of OPA tumor cells as well as expression of JSRV.
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Enhanced proliferation of primary rat type II pneumocytes by Jaagsiekte Sheep Retrovirus envelope protein.
Virology, 2011Co-Authors: Chassidy Johnson, Sohail Jahid, Dennis R. Voelker, Hung FanAbstract:Jaagsiekte Sheep Retrovirus (JSRV) is the causative agent of a contagious lung cancer in Sheep. The envelope protein (Env) is the oncogene, as it can transform cell lines in culture and induce tumors in animals, although the mechanisms for transformation are not yet clear because a system to perform transformation assays in differentiated type II pneumocytes does not exist. In this study we report culture of primary rat type II pneumocytes in conditions that favor prolonged expression of markers for type II pneumocytes. Env-expressing cultures formed more colonies that were larger in size and were viable for longer periods of time compared to vector control samples. The cells that remained in culture longer were confirmed to be derived from type II pneumocytes because they expressed surfactant protein C, cytokeratin, displayed alkaline phosphatase activity and were positive for Nile red. This system will be useful to study JSRV Env in the targets of transformation.
Massimo Palmarini - One of the best experts on this subject based on the ideXlab platform.
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Structure of the Capsid Amino-Terminal Domain from the BetaRetrovirus, Jaagsiekte Sheep Retrovirus.
Journal of Molecular Biology, 2008Co-Authors: Gulnahar B. Mortuza, David C. Goldstone, Clare Pashley, Lesley F. Haire, Massimo Palmarini, Jonathan Paul Stoye, William R Taylor, Ian A TaylorAbstract:Jaagsiekte Sheep Retrovirus is a betaRetrovirus and the causative agent of pulmonary adenocarcinoma, a transmissible lung tumour of Sheep. Here we report the crystal structure of the capsid amino-terminal domain and examine the self-association properties of Jaagsiekte Sheep Retrovirus capsid. We find that the structure is remarkably similar to the amino-terminal domain of the alphaRetrovirus, avian leukosis virus, revealing a previously undetected evolutionary similarity. Examination of capsid self-association suggests a mode of assembly not driven by the strong capsid carboxy-terminal domain interactions that characterise capsid assembly in the lentiviruses. Based on these data, we propose this structure provides a model for the capsid of betaRetroviruses including the HML-2 family of endogenous human betaRetroviruses.
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Jaagsiekte Sheep Retrovirus
Encyclopedia of Virology, 2008Co-Authors: J. M. Sharp, M De Las Heras, Thomas E. Spencer, Massimo PalmariniAbstract:Jaagsiekte Sheep Retrovirus (JSRV) and the related small ruminant betaRetroviruses are a fascinating group of viruses with unique characteristics that are of broad interest through their veterinary, comparative medical and biological importance. JSRV is the causative agent of ovine pulmonary adenocarcinoma (OPA), an important viral disease of Sheep and an outbred animal model for human lung adenocarcinoma. The mechanisms followed by JSRV to transform cells are unique among oncogenic Retroviruses as the viral envelope glycoprotein (Env) functions as a dominant oncoprotein. The enzootic nasal tumor virus (ENTV) is also an oncogenic Retrovirus highly related both phylogenetically and biologically to JSRV. ENTV induces a contagious tumor of the mucosal nasal glands in Sheep and goats. Interestingly, Sheep, goats, and most species belonging to the subfamily of the Caprinae, have stably integrated in their genome endogenous Retroviruses highly related to ENTV and JSRV (hence the name enJSRVs). enJSRVs are expressed, particularly in the genital tract epithelia of the ewe. Intriguingly, enJSRVs appear critical for Sheep placental development during the pre-implantation period and therefore represent a powerful example on how viruses can shape mammalian biology.
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Jaagsiekte Sheep Retrovirus is not detected in human lung adenocarcinomas expressing antigens related to the Gag polyprotein of betaRetroviruses
Cancer Letters, 2007Co-Authors: Marcelo De Las Heras, A Ortin, Pablo R. Murcia, Javier Azúa, Luis Borderías, Ramiro Álvarez, José Antonio Jiménez-más, Antonio Marchetti, Massimo PalmariniAbstract:A proportion of human lung adenocarcinomas (hLACs) express an antigen related to the major capsid protein (CA) of Jaagsiekte Sheep Retrovirus (JSRV), a BetaRetrovirus that causes a transmissible lung cancer in Sheep. In this study, we have investigated whether JSRV or related betaRetroviruses are expressed in hLACs. Results obtained indicate that JSRV is not associated with human lung adenocarcinomas. However, a proportion of hLACs reacted positively in immunohistochemistry with antibodies specific towards different domains of the JSRV Gag suggesting that a bona fide Retrovirus antigen could be expressed in these tumours. Further studies will be necessary to ascertain whether the detection of antigens cross-reacting with betaRetrovirus Gag antisera in some hLACs is due to expression of a human endogenous Retrovirus or, more unlikely, of an uncharacterized exogenous Retrovirus.
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The transdominant endogenous Retrovirus enJS56A1 associates with and blocks intracellular trafficking of Jaagsiekte Sheep Retrovirus gag
Journal of Virology, 2007Co-Authors: P. R. Murcia, Frederick Arnaud, Massimo PalmariniAbstract:The Sheep genome harbors approximately 20 endogenous Retroviruses (enjSRVs) highly related to the exogenous Jaagsiekte Sheep Retrovirus (JSRV). One of the enJSRV loci, enJS56A1, acts as a unique restriction factor by blocking JSRV in a transdominant fashion at a late stage of the retroviral cycle. To better understand the molecular basis of this restriction (termed JLR, for JSRV late restriction), we functionally characterized JSRV and enJS56A1 Gag proteins. We identified the putative JSRV Gag membrane binding and late domains and determined their lack of involvement in JLR. In addition, by using enJS56A1 truncation mutants, we established that the entire Gag protein is necessary to restrict JSRV exit. By using differentially tagged viruses, we observed, by confocal microscopy, colocalization between JSRV and enJS56A1 Gag proteins. By coimmunoprecipitation and molecular complementation analyses, we also revealed intracellular association and likely coassembly between JSRV and enJS56A1 Gag proteins. Interestingly, JSRV and enJS56A1 Gag proteins showed distinct intracellular targeting: JSRV exhibited pericentrosomal accumulation of Gag staining, while enJS56A1 Gag did not accumulate in this region. Furthermore, the number of cells displaying pericentrosomal JSRV Gag was drastically reduced in the presence of enJS56A1. We identified amino acid residue R21 in JSRV Gag as the primary determinant of centrosome targeting. We concluded that JLR is dependent on a Gag-Gag interaction between enJS56A1 and JSRV leading to altered cellular localization of the latter.
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expression of the Jaagsiekte Sheep Retrovirus envelope glycoprotein is sufficient to induce lung tumors in Sheep
Journal of Virology, 2006Co-Authors: Marco Caporale, Christina Cousens, Patrizia Centorame, Marcelo De Las Heras, Chiara Pinoni, Massimo PalmariniAbstract:Jaagsiekte Sheep Retrovirus (JSRV) is the causative agent of ovine pulmonary adenocarcinoma (OPA). The expression of the JSRV envelope (Env) alone is sufficient to transform a variety of cell lines in vitro and induce lung cancer in immunodeficient mice. In order to determine the role of the JSRV Env in OPA tumorigenesis in Sheep, we derived a JSRV replication-defective virus (JS-RD) which expresses env under the control of its own long terminal repeat (LTR). JS-RD was produced by transiently transfecting 293T cells with a two plasmid system, involving (i) a packaging plasmid, with the putative JSRV packaging signal deleted, expressing the structural and enzymatic proteins Gag, Pro, and Pol, and (ii) a plasmid which expresses env in trans for JS-RD particles and provides the genomes necessary to deliver JSRV env upon infection. During the optimization of the JS-RD system we determined that both R-U5 (in the viral 5' LTR) and the env region are important for JSRV particle production. Two independent experimental transmission studies were carried out with newborn lambs. Four of five lambs inoculated with JS-RD showed OPA lesions in the lungs at various times between 4 and 12 months postinoculation. Abundant expression of JSRV Env was detected in tumor cells of JS-RD-infected animals and PCR assays confirmed the presence of the deleted JS-RD genome. These data strongly suggest that the JSRV Env functions as a dominant oncoprotein in the natural immunocompetent host and that JSRV can induce OPA in the absence of viral spread.
Shan-lu Liu - One of the best experts on this subject based on the ideXlab platform.
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evidence against a role for Jaagsiekte Sheep Retrovirus in human lung cancer
Retrovirology, 2017Co-Authors: Dusty A Miller, Shan-lu Liu, Marcelo De Las Heras, Fushun Zhang, Andrew E Vaughan, Thomas L Vaughan, Raul RosadioAbstract:Jaagsiekte Sheep Retrovirus (JSRV) causes a contagious lung cancer in Sheep and goats that can be transmitted by aerosols produced by infected animals. Virus entry into cells is initiated by binding of the viral envelope (Env) protein to a specific cell-surface receptor, Hyal2. Unlike almost all other Retroviruses, the JSRV Env protein is also a potent oncoprotein and is responsible for lung cancer in animals. Of concern, Hyal2 is a functional receptor for JSRV in humans. We show here that JSRV is fully capable of infecting human cells, as measured by its reverse transcription and persistence in the DNA of cultured human cells. Several studies have indicated a role for JSRV in human lung cancer while other studies dispute these results. To further investigate the role of JSRV in human lung cancer, we used highly-specific mouse monoclonal antibodies and a rabbit polyclonal antiserum against JSRV Env to test for JSRV expression in human lung cancer. JSRV Env expression was undetectable in lung cancers from 128 human subjects, including 73 cases of bronchioalveolar carcinoma (BAC; currently reclassified as lung invasive adenocarcinoma with a predominant lepidic component), a lung cancer with histology similar to that found in JSRV-infected Sheep. The BAC samples included 8 JSRV DNA-positive samples from subjects residing in Sardinia, Italy, where Sheep farming is prevalent and JSRV is present. We also tested for neutralizing antibodies in sera from 138 Peruvians living in an area where Sheep farming is prevalent and JSRV is present, 24 of whom were directly exposed to Sheep, and found none. We conclude that while JSRV can infect human cells, JSRV plays little if any role in human lung cancer.
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fusogenicity of Jaagsiekte Sheep Retrovirus envelope protein is dependent on low ph and is enhanced by cytoplasmic tail truncations
Journal of Virology, 2008Co-Authors: Marceline Côté, Yi-min Zheng, Lorraine M. Albritton, Shan-lu LiuAbstract:Jaagsiekte Sheep Retrovirus (JSRV) envelope (Env) is an active oncogene responsible for neoplastic transformation in animals and cultured cells. In this study, we used syncytium induction and fluorescence-based cell fusion assays to investigate JSRV Env fusion and its modulation by the cytoplasmic tail (CT). We found that JSRV Env induced syncytia in cells overexpressing the receptor for JSRV and that a low pH was required for this process to occur. Fusion kinetics studies revealed that cell-cell fusion by JSRV Env at neutral pH was poor, taking up to a day, in sharp contrast to fusion at low pH, which peaked within 2 min following a low-pH trigger. Deletion of the C-terminal 7 or 16 amino acids of the JSRV Env CT had no or little effect on fusion, yet additional truncation toward the membrane-spanning domain, resulting in mutants retaining as little as 1 amino acid of the CT, led to progressively increased syncytium formation at neutral pH that was further enhanced by low-pH treatment. Notably, the severely truncated mutants showed elevated levels of surface subunits in culture medium, suggesting that the CT truncations resulted in conformational changes in the ectodomain of Env that impaired surface subunit associations. Taken together, this study reveals for the first time that the fusion activity of the JSRV Env protein is dependent on a low pH and is modulated by the CT, whose truncation overcomes, at least partially, the low-pH requirement for fusion and enhances Env fusion activity and kinetics.
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Jaagsiekte Sheep Retrovirus Utilizes a pH-Dependent Endocytosis Pathway for Entry
Journal of Virology, 2007Co-Authors: Pascale Bertrand, Marceline Côté, Yi-min Zheng, Lorraine M. Albritton, Shan-lu LiuAbstract:Using Moloney murine leukemia virus pseudovirions bearing the envelope protein of Jaagsiekte Sheep Retrovirus (JSRV), we report here that entry was weakly inhibited by lysosomotropic agents but was profoundly blocked by bafilomycin A1 (BafA1). Kinetics studies revealed that JSRV entry is a slow process and was substantially blocked by a dominant-negative mutant of dynamin. Interestingly, a low-pH pulse overcame the BafA1 block to JSRV infection, although this occurred only if virus-bound cells were preincubated at 37°C, consistent with a very early entry event such as endocytosis being required before the low-pH-dependent step occurs. Moreover, JSRV pseudovirions were resistant to low-pH inactivation. Altogether, this study reveals that JSRV utilizes a pH-dependent, dynamin-associated endocytosis pathway for entry that differs from the classical pH-dependent entry pathway of vesicular stomatitis virus.
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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, 2004Co-Authors: Dusty A Miller, Neal Van Hoeven, Shan-lu LiuAbstract:Background The envelope (Env) protein of Jaagsiekte Sheep Retrovirus (JSRV) can transform cells in culture and is likely to be the main factor responsible for lung cancer induction by JSRV in animals. A recent report indicates that the epithelial-cell transforming activity of JSRV Env depends on activation of the cell-surface receptor tyrosine kinase Mst1r (called RON for the human and Stk for the rodent orthologs). In the immortalized line of human epithelial cells used (BEAS-2B cells), the virus receptor Hyal2 was found to bind to and suppress the activity of RON. When Env was expressed it bound to Hyal2 causing its degradation, release of RON activity from Hyal2 suppression, and activation of pathways resulting in cell transformation.
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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, 2004Co-Authors: A. Dusty Miller, Neal Van Hoeven, Shan-lu LiuAbstract:Background The envelope (Env) protein of Jaagsiekte Sheep Retrovirus (JSRV) can transform cells in culture and is likely to be the main factor responsible for lung cancer induction by JSRV in animals. A recent report indicates that the epithelial-cell transforming activity of JSRV Env depends on activation of the cell-surface receptor tyrosine kinase Mst1r (called RON for the human and Stk for the rodent orthologs). In the immortalized line of human epithelial cells used (BEAS-2B cells), the virus receptor Hyal2 was found to bind to and suppress the activity of RON. When Env was expressed it bound to Hyal2 causing its degradation, release of RON activity from Hyal2 suppression, and activation of pathways resulting in cell transformation.
A. Dusty Miller - One of the best experts on this subject based on the ideXlab platform.
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Evidence against a role for Jaagsiekte Sheep Retrovirus in human lung cancer
Retrovirology, 2017Co-Authors: A. Dusty Miller, Fushun Zhang, Andrew E Vaughan, Thomas L Vaughan, Raul Rosadio, Marcelo De Las Heras, Jingyou Yu, Stefano Rocca, Giuseppe Palmieri, James J. GoedertAbstract:Background Jaagsiekte Sheep Retrovirus (JSRV) causes a contagious lung cancer in Sheep and goats that can be transmitted by aerosols produced by infected animals. Virus entry into cells is initiated by binding of the viral envelope (Env) protein to a specific cell-surface receptor, Hyal2. Unlike almost all other Retroviruses, the JSRV Env protein is also a potent oncoprotein and is responsible for lung cancer in animals. Of concern, Hyal2 is a functional receptor for JSRV in humans. Results We show here that JSRV is fully capable of infecting human cells, as measured by its reverse transcription and persistence in the DNA of cultured human cells. Several studies have indicated a role for JSRV in human lung cancer while other studies dispute these results. To further investigate the role of JSRV in human lung cancer, we used highly-specific mouse monoclonal antibodies and a rabbit polyclonal antiserum against JSRV Env to test for JSRV expression in human lung cancer. JSRV Env expression was undetectable in lung cancers from 128 human subjects, including 73 cases of bronchioalveolar carcinoma (BAC; currently reclassified as lung invasive adenocarcinoma with a predominant lepidic component), a lung cancer with histology similar to that found in JSRV-infected Sheep. The BAC samples included 8 JSRV DNA-positive samples from subjects residing in Sardinia, Italy, where Sheep farming is prevalent and JSRV is present. We also tested for neutralizing antibodies in sera from 138 Peruvians living in an area where Sheep farming is prevalent and JSRV is present, 24 of whom were directly exposed to Sheep, and found none. Conclusions We conclude that while JSRV can infect human cells, JSRV plays little if any role in human lung cancer.
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Ability of Hyaluronidase 2 To Degrade Extracellular Hyaluronan Is Not Required for Its Function as a Receptor for Jaagsiekte Sheep Retrovirus
Journal of Virology, 2007Co-Authors: Vladimir Vigdorovich, A. Dusty Miller, Roland K. StrongAbstract:Jaagsiekte Sheep Retrovirus (JSRV) uses hyaluronidase 2 (Hyal2) as a cell entry receptor. By making inactivating mutations to the catalytic residues of human Hyal2, we found that hyaluronidase activity was dispensable for its receptor function. The affinities of the JSRV envelope glycoprotein for Hyal2 and the Hyal2 mutant were similar, and hyaluronan did not block either high-affinity interaction or virus infection. While generating the Hyal2 mutant, we discovered that our previous analysis of the hyaluronidase activity of Hyal2 was affected by a contaminating hyaluronan lyase, which we have identified as the occlusion-derived baculovirus E66 protein of the recombinant baculovirus used to produce Hyal2. We now report that purified human Hyal2 is a weak acid-active hyaluronidase.
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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, 2006Co-Authors: Sarah K. Wootton, Christine L. Halbert, A. Dusty MillerAbstract: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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Lung cancer induced in mice by the envelope protein of Jaagsiekte Sheep Retrovirus (JSRV) closely resembles lung cancer in Sheep infected with JSRV
Retrovirology, 2006Co-Authors: Sarah K. Wootton, James C. Demartini, Michael J. Metzger, Kelly L. Hudkins, Charles E. Alpers, Denis York, A. Dusty MillerAbstract:Background Jaagsiekte Sheep Retrovirus (JSRV) causes a lethal lung cancer in Sheep and goats. Expression of the JSRV envelope (Env) protein in mouse lung, by using a replication-defective adeno-associated virus type 6 (AAV6) vector, induces tumors resembling those seen in Sheep. However, the mouse and Sheep tumors have not been carefully compared to determine if Env expression alone in mice can account for the disease features observed in Sheep, or whether additional aspects of virus replication in Sheep are important, such as oncogene activation following Retrovirus integration into the host cell genome.
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Amino acid residues that are important for Hyal2 function as a receptor for Jaagsiekte Sheep Retrovirus
Retrovirology, 2005Co-Authors: Fuh-mei Duh, Clarissa Dirks, Michael I Lerman, A. Dusty MillerAbstract:Background Infection by Jaagsiekte Sheep Retrovirus (JSRV) and by enzootic nasal tumor virus (ENTV) depends on cell-surface expression of the virus entry receptor, hyaluronidase 2 (Hyal2). Human Hyal2 binds the envelope (Env) proteins of these viruses and is functional as a receptor, but Hyal2 from mice does not bind Env nor does it mediate entry of either virus. Here we have explored the amino acid determinants that account for the difference in receptor function.
Alan W. Flake - One of the best experts on this subject based on the ideXlab platform.
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Jaagsiekte Sheep Retrovirus pseudotyped lentiviral vector-mediated gene transfer to fetal ovine lung
Gene Therapy, 2012Co-Authors: Marcus G. Davey, Philip W. Zoltick, Carlyn A. Todorow, Maria P. Limberis, Eduardo Ruchelli, Holly L. Hedrick, Alan W. FlakeAbstract:Viral vector-mediated gene transfer to the postnatal respiratory epithelium has, in general, been of low efficiency due to physical and immunological barriers, non-apical location of cellular receptors critical for viral uptake and limited transduction of resident stem/progenitor cells. These obstacles may be overcome using a prenatal strategy. In this study, HIV-1-based lentiviral vectors (LVs) pseudotyped with the envelope glycoproteins of Jaagsiekte Sheep Retrovirus (JSRV-LV), baculovirus GP64 (GP64-LV), Ebola Zaire-LV or vesicular stomatitis virus (VSVg-LV) and the adeno-associated virus-2/6.2 (AAV2/6.2) were compared for in utero transfer of a green fluorescent protein (GFP) reporter gene to ovine lung epithelium between days 65 and 78 of gestation. GFP expression was examined on day 85 or 136 of gestation (term is ∼145 days). The percentage of the respiratory epithelial cells expressing GFP in fetal Sheep that received the JSRV-LV (3.18 × 10^8–6.85 × 10^9 viral particles per fetus) was 24.6±0.9% at 3 weeks postinjection (day 85) and 29.9±4.8% at 10 weeks postinjection (day 136). Expression was limited to the surface epithelium lining fetal airways
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Jaagsiekte Sheep Retrovirus pseudotyped lentiviral vector-mediated gene transfer to fetal ovine lung
Gene Therapy, 2011Co-Authors: Marcus G. Davey, Philip W. Zoltick, Carlyn A. Todorow, Maria P. Limberis, Eduardo Ruchelli, Holly L. Hedrick, Alan W. FlakeAbstract:Jaagsiekte Sheep Retrovirus pseudotyped lentiviral vector-mediated gene transfer to fetal ovine lung