We will continue our studies on factors influencing in vivo pathogenesis and tissue specific infection by Moloney murine leukemia virus (M-MuLV), which induces T-lymphoma in mice. These experiments will exploit novel LTR variants of M-MuLV that show altered disease patterns or tissue distributions. There are three major aims: 1) Studies on MCFs and preleukemic events induced by M-MuLV. Comparisons between wild-type and poorly leukemogenic Mo+PyF1O1 M-MuLV identified a preleukemic state of generalized hematopoietic hyperplasia in the spleen. This preleukemic state involves MCF recombinant viruses. In tile proposed experiments, we will study events involved in MCF formation in vivo. We will identify cells in the mouse involved in both MCF generation and propagation by a combination of virological and immunological approaches. The validity of these results will be tested by studying animals infected with Mo+PyF101 M-MULV, since they do not develop MCFs in vivo. The molecular basis for the inability of Mo+PyF101 MCFs to propagate in vivo will be studied. 2) Leukemogenesis by enhancer variants of M-MuLV. In contrast to wildtype M-MuLV, Delta Mo+SV M-MuLV induces B-lymphoma with extremely long latency. The mechanisms of leukemogenesis will be studied, including virological parameters, and activation of proto-oncogenes. The possibility of novel activated proto-oncogenes will be tested by PCR cloning. Sublethal irradiation markedly accelerates leukemogenesis by Delta Mo + SV M-MuLV, and the mechanism of this will be explored. A second virus, Delta 27A M-MuLV induces leukemia of diverse types, including T-lymphoid, B-lymphoid, myeloid and erythroid. Leukemogenesis by this virus will be explored as well. 3) Tissue distribution of Delta Mo+TTR(PD) M-MuLV. This virus is driven by regulatory elements of the mouse transthyretin (TTR) gene. It shows novel expression sites in vivo: the brain and (in some animals) the liver. The particular brain cells infected will be identified, and we will also seek co-factors for virus expression in the liver. These experiments will provide insight into the multi-step leukemogenic process from M-MuLv, they may also elucidate factors involved in tissue-specific virus infection in vivo.
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