FUNCTION OF A UNIQUE SEQUENCE MOTIF IN THE LONG TERMINAL REPEAT OF FELINE LEUKEMIA-VIRUS ISOLATED FROM AN UNUSUAL SET OF NATURALLY-OCCURRING TUMORS

Feline leukemia virus (FeLV) proviruses have been characterized from n aturally occurring non-B-cell, non-T-cell tumors occurring in the sple ens of infected cats. These proviruses exhibit a unique sequence motif in the long terminal repeat (LTR), namely, a 21-bp tandem triplicatio n beginning 25 bp downstream of the enhancer, The repeated finding of the triplication-containing LTR in non-B-cell, non-TT-cell lymphomas o f the spleen suggests that the unique LTR is an essential participant in the development of tumors of this particular phenotype. The nucleot ide sequence of the triplication-containing LTR most closely resembles that of FeLV subgroup C. Studies performed to measure the ability of the triplication-containing LTR to modulate gene expression indicate t hat the 21-bp triplication provides transcriptional enhancer function to the LTR that contains it and that it substitutes at least in part f or the duplication of the enhancer. The 21-bp triplication confers a b ona fide enhancer function upon LTR-directed reporter gene expression; however, the possibility of a spacer function was not eliminated, The studies demonstrate further that the triplication-containing LTR acts preferentially in a cell-type-specific manner, i.e., it is U-fold mor e active in K-562 cells than is an LTR lacking the triplication, A rec ombinant, infectious FeLV bearing the 21-bp triplication in U3 was con structed. Cells infected with the recombinant were shown to accumulate higher levels of viral RNA transcripts and virus particles in culture supernatants than did cells infected with the parental type. The trip lication-containing LTR is implicated in the induction of tumors of a particular phenotype, perhaps through transcriptional regulation of th e virus and/or adjacent cellular genes, in the appropriate target cell .