We propose to study the molecular basis for virus-induced malignant tumors and immune-suppression. Malignant fibroma virus (MV) produces disseminated tumors and severe immunosuppression. A related virus, Shope fibroma virus (SFV), produces only a local tumor and does not alter-immune function. A single MV gene transfers from MV to SFV the ability to replicate in lymphocytes. Transferring this gene allows subsequent development of other phenomena associated with MV's virulence: tumor dissemination and suppression of immune function in - vivo. This gene encodes orf C-7 in MV's Bam HI """"""""C"""""""" fragment. Its SFV homolog is D-7, from SFV's Bam HI """"""""D"""""""" fragment. C-7 and D-7 are early transcription factors (ETF) and differ somewhat in structure. We propose here to study the structure of virulent recombinant-viruses that we have on hand, in which a part of C-7 has been transferred to SF. We will ascertain the structure and location of the MV insert. We have generated, and propose here to characterize, lymphocytotropic recombinant viruses in which a very small (0.7 kb) portion of C-7 orf is transferred to SFV. The location and structure of the MV insert in these new recombinants will be studied. The ability of these new recombinants to replicate in lymphocytes, suppress immune function and cause disseminated tumors will be evaluated, as will the structure of the transferred MV DNA fragment. MV C-7 and SFV D-7 ETF proteins differ by only 6 amino acids in the region that transfers lymphocytotropism from MV to SFV, mutant orf's will be made at each codon to identify the specific structural -- determinants for this aspect of virus virulence. We will also study whether C-7 orf is necessary as well as sufficient for replication in lymphocytes, by making obverse recombinants- in which C-7 is replaced in MV by its SFV homolog, D-7-will be made and studied for their ability to replicate in lymphocytes and for their clinical and immunologic activities in vitro and in vivo. Therefore, we propose to identify genetic basis for the ability of a virus to replicate in lymphocytes and to set into motion profound vi virus-induced immune dysfunction and tumor dissemination. In so doing, the interrelationships of these different facets of virulence will be elucidated.
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