The objective of the proposed studies of CWD/J mice is to characterize a novel mechanism of retroviral oncogenesis, one that is mediated primarily by the envelope genes of recombinant murine leukemia viruses (MuLV). In particular, they will clarify the role of host factors in regulating the structure and function of the envelope gene sequences that facilitate leukemogenesis by recombinant MuLVs. The results will provide a better understanding of retrovirus: host interactions that are associated with the development of malignant disease. Viruses isolated from CWD/J mice will be analyzed in leukemia acceleration assays to determine the relationship between recombinant MuLVs and the development of spontaneous non-thymic lymphomas in these animals. The structure and the nucleic acid sequence of the env and U3 region of molecular clones of the CWD proviruses will be compared with those of other apathogenic and leukemogenic MuLVs in hopes of identifying regions of the CWD viral genome that mediate pathogenicity. To confirm the contribution of specific regions of the viral genome to pathogenicity, the biologic properties of natural CWD recombinant viruses and those derived from chimeric proviruses constructed in vitro will be determined. Host genes that may influence the susceptibility of CWD/J mice to the development of non-thymic lymphomas will also be studied. Analysis of the immunophenotype of spontaneous and virus-induced CWD lymphomas will be performed to see if host or viral genes regulate the phenotype of the disease. Northern blot and S1 nuclease experiments will be used to identify RNAs of endogenous proviruses that are expressed in various CWD tissues and may be the source of the envelope genes found in the CWD recombinant viruses.

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National Cancer Institute (NCI)
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Experimental Virology Study Section (EVR)
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University of Virginia
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Lawrenz-Smith, S C; Thomas, C Y (1995) The E47 transcription factor binds to the enhancer sequences of recombinant murine leukemia viruses and influences enhancer function. J Virol 69:4142-8
Lawrenz-Smith, S C; Massey, A C; Innes, D J et al. (1994) Pathogenic determinants in the U3 region of recombinant murine leukemia viruses isolated from CWD and HRS/J mice. J Virol 68:5174-83
Massey, A C; Lawrenz-Smith, S C; Innes, D J et al. (1994) Origins of enhancer sequences of recombinant murine leukemia viruses from spontaneous B- and T-cell lymphomas of CWD mice. J Virol 68:3773-83
Thomas, C Y; Coppola, M A; Nuckols, J D et al. (1993) An increase in disease latency is associated with a host-dependent selection for recombinant murine leukemia viruses with substitutions in the p15E (TM) gene. J Virol 67:294-304
Thomas, C Y; Nuckols, J D; Murphy, C et al. (1993) Generation and pathogenicity of an NB-tropic SL3-3 murine leukemia virus. Virology 193:1013-7
Massey, A C; Coppola, M A; Thomas, C Y (1990) Origin of pathogenic determinants of recombinant murine leukemia viruses: analysis of Bxv-1-related xenotropic viruses from CWD mice. J Virol 64:5491-9
Thomas, C Y; Coppola, M A; Holland, C A et al. (1990) Oncogenicity and U3 region sequences of class II recombinant MuLVs of CWD mice. Virology 176:166-77
Coppola, M A; Thomas, C Y (1990) A host gene regulates the structure of the transmembrane envelope protein of murine leukemia viruses. J Exp Med 171:1739-52
Thomas, C Y; Buxton, V K; Roberts, J S et al. (1989) Phenotypic heterogeneity of spontaneous lymphomas of CWD mice. Blood 73:240-7
Thomas, C Y; Roberts, J S; Buxton, V K (1988) Mechanism of selection of class II recombinant murine leukemia viruses in the highly leukemic strain CWD. J Virol 62:1158-66

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