Transforming viruses spontaneously arise from nontransforming reticuloendotheliosis virus strain T-derived viruses as a result of increased accumulation of spliced viral RNA.

The highly oncogenic avian retrovirus reticuloendotheliosis virus strain T (Rev-T) contains a substitution of the oncogene v-rel for much of env and a deletion of gag and pol relative to the helper virus Rev-A. Replacement of gag and pol sequences in Rev-T suppresses transformation by reducing the accumulation of spliced viral mRNA and v-rel protein in infected cells (C. K. Miller and H. M. Temin, J. Virol 58:75-80, 1986). After infection of spleen cells with viruses containing gag and pol sequences, revertant viruses that are strongly transforming were found. Approximately three-fourths of the revertant viruses appeared structurally the same as the parental virus, and approximately one-fourth of the revertant viruses had large deletions (similar in size and location to the deletion in Rev-T). Two revertant viruses that appeared structurally the same as the parental virus were molecularly cloned. The regions sufficient to change the parental virus to a strongly transforming virus were determined by construction of recombinant viruses. In one revertant virus, the region sufficient for transformation contained a 327-base-pair insertion 5' of the 3' splice site used by Rev-T. In the other revertant virus, the region sufficient for transformation contained a 1-base-pair transition and a deletion of one copy of a 9-base-pair direct repeat, both 3' of the 3' splice site used by Rev-T. These differences resulted in the accumulation of increased levels of subgenomic v-rel mRNA and protein, ultimately leading to transformation.