DELETION OF THE GROWTH-FACTOR GENE RELATED TO EGF AND TGF-ALPHA REDUCES VIRULENCE OF MALIGNANT RABBIT FIBROMA VIRUS

The role of the epidermal growth factor homologue in malignant rabbit fibroma virus (MRV) pathogenicity was investigated by constructing a viral growth factor deletion mutant (MRV-GF-). Since MRV is a recombinant virus with a myxoma virus background but possesses some terminal sequences derived from Shope fibroma virus, the growth factor gene in MRV is in fact identical to Shope fibroma growth factor (SFGF). Although no significant differences were detected in the in vitro characteristics of MRV and MRV-GF-, a pronounced attenuation was observed after inoculation of the test rabbits with MRV-GF-, Animals infected with wild-type MRV uniformly developed a fatal syndrome involving disseminated tumors accompanied by purulent conjunctivitis and rhinitis. In contrast, although MRV-GF- recipients developed similar initial signs of the MRV disease syndrome, 75% of these animals completely recovered from the viral and secondary bacterial infections and became immune to subsequent MRV challenge. Tumors in MRV-GF- recipients displayed earlier and more prominent inflammatory reactions than their wild-type MRV counterparts and contained fewer proliferating cells. Squamous metaplasia and hyperplasia of target epithelia were less pronounced in MRV-GF- than in MRV infection. We conclude that SFGF is a major virulence factor in MRV infection and is responsible for at least some of the cellular proliferation observed at tumor sites. In addition, the diminished ability of MRV-GF- to cause hyperplasia in nasal and conjunctival epithelia may decrease the extent of gram negative bacterial overgrowth as compared to the parental virus and hence contribute to the dramatic reduction in the lethality of MRV-GF- infection. © 1992.