Tumorigenic poxviruses: analysis of viral DNA sequences implicated in the tumorigenicity of Shope fibroma virus and malignant rabbit virus.

The DNA sequence has been determined for a 7-kb region within the terminal inverted repeats (TIR) of Shope fibroma virus (SFV), a poxvirus which induces benign fibromas in rabbits. This region of the SFV TIR, which flanks the junction of the TIR with the unique internal sequences of the viral genome, had previously been shown to be also present in the genome of malignant rabbit virus (MRV), a hybrid poxvirus derived from a recombination event between SFV and a related leporipoxvirus, myxoma. Unlike SFV, the recombinant MRV induces an invasive profile of tumors in infected rabbits, but the capacity to induce proliferant fibromas appears to have been derived from SFV. These SFV DNA sequences have been analyzed and their genetic organization shows a unique tandem arrangement of three large open reading frames (ORFs) which share considerable homology with each other. Very short spacer sequences are present between the majority of ORFs, all of which are transcribed toward the terminal hairpins of SFV. Unusual dyad symmetries flank two of the most closely related ORFs and evidence is presented that one SFV ORF (T9-L) which maps precisely at the TIR/unique sequence boundary was truncated during transposition to the left terminus from a progenitor copy (T9-R) at the right terminus. The origin of these putative viral genes is considered in light of the recent observation (C. Upton and G. McFadden, 1986, Mol. Cell. Biol. 6, 265-276) that a subset of this region of the SFV genome is closely related to, and may have been originally derived from, an endogenous covalently closed circular plasmid species detected in uninfected rabbit cells.