In this proposal, we will study the Jaagsiekte Sheep Retrovirus (JSRV) that induces ovine pulmonary carcinoma (PC) in sheep. OPC is an infectious neoplasm of sheep that occurs in many geographical locations. It is analogous to human brochiolar aveolar carcinoma (BAC) that accounts for approximately 25% of lung cancer in humans. OPC and BAC are neoplasms of secretory type II pneumocytes (that make pulmonary surfactants) and Clara cells. Previous experiments by others have made a strong case that the etiologic agent of PC is a type D retrovirus (JSRV). The genome organization of JSRV has been deduced from a series of cDNA clones isolated from the lung fluid of a sheep with OPC. However, the previous JSRV clone was not infectious. In preliminary experiments, we have isolated a complete JSRV pro-virus from a field isolate of OPC, JSRV-21. Direct, intratracheal injection of JSRV-21 DNA into newborn lambs resulted in infection, as detected by hemi-nested PCR of PBMCs, lymph nodes and lung tissue. We also have been able to generate substantial quantities of JSRV virus by transfection of modified JSRV-21 plasmids into human 293T cells. These and related regents allow a focused study on the molecular and oncogenic properties of JSRV. In this proposal, we will carry out the following experiments: 1) Identification of an oncogenic clone of JSRV; 2) Molecular characterization of JSRV; 3) Development of an in vitro culture system for JSRV; and 4) Investigation of the role of orf-X in JSRV infectivity and oncogenicity. These experiments will provide insight into JSRV-induced lung cancer in sheep, and possibly into human BAC.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Virology Study Section (VR)
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Cole, John S
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University of California Irvine
Schools of Arts and Sciences
United States
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Johnson, Chassidy; Jahid, Sohail; Voelker, Dennis R et al. (2011) Enhanced proliferation of primary rat type II pneumocytes by Jaagsiekte sheep retrovirus envelope protein. Virology 412:349-56
Dakessian, Raffy M; Fan, Hung (2008) Specific in vivo expression in type II pneumocytes of the Jaagsiekte sheep retrovirus long terminal repeat in transgenic mice. Virology 372:398-408
Cousens, Chris; Maeda, Naoyoshi; Murgia, Claudio et al. (2007) In vivo tumorigenesis by Jaagsiekte sheep retrovirus (JSRV) requires Y590 in Env TM, but not full-length orfX open reading frame. Virology 367:413-21
McGee-Estrada, Kathleen; Fan, Hung (2007) Comparison of LTR enhancer elements in sheep beta retroviruses: insights into the basis for tissue-specific expression. Virus Genes 35:303-12
Hallwirth, Claus; Maeda, Naoyoshi; York, Denis et al. (2005) Variable regions 1 and 2 (VR1 and VR2) in JSRV gag are not responsible for the endogenous JSRV particle release defect. Virus Genes 30:59-68
Maeda, Naoyoshi; Inoshima, Yasuo; Fruman, David A et al. (2003) Transformation of mouse fibroblasts by Jaagsiekte sheep retrovirus envelope does not require phosphatidylinositol 3-kinase. J Virol 77:9951-9
Fan, H; Palmarini, M; DeMartini, J C (2003) Transformation and oncogenesis by jaagsiekte sheep retrovirus. Curr Top Microbiol Immunol 275:139-77
McGee-Estrada, Kathleen; Palmarini, Massimo; Fan, Hung (2002) HNF-3beta is a critical factor for the expression of the Jaagsiekte sheep retrovirus long terminal repeat in type II pneumocytes but not in Clara cells. Virology 292:87-97
Palmarini, Massimo; Murgia, Claudio; Fan, Hung (2002) Spliced and prematurely polyadenylated Jaagsiekte sheep retrovirus-specific RNAs from infected or transfected cells. Virology 294:180-8
Palmarini, M; Fan, H (2001) Retrovirus-induced ovine pulmonary adenocarcinoma, an animal model for lung cancer. J Natl Cancer Inst 93:1603-14

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