Unique LTR and Su sequence motifs in natural isolates of feline leukemia virus
Description
Feline leukemia virus (FeLV), like other naturally occurring retroviruses, is characterized by a high degree of genetic diversity. In a group of naturally-occurring non-B-cell non-T-cell lymphomas, classified anatomically as multicentric, the FeLV LTR exhibits a unique structural motif in the LTR comprised of a 21-bp tandem triplication downstream of a single cope of the enhancer. The triplication sequence is precisely conserved among 8 independent multicentric lymphomas collected in a geographic cluster. Previous studies indicate that the 21-bp triplication provides an enhancer function to the LTR that contains it, and that it substitutes at least in part for the duplication of the enhancer. These studies predict that the FeLV LTR containing the triplication would confer a replicative advantage on the virus that contains it, in a cell type-specific manner. To test that prediction, in this study, a set of recombinant FeLVs was developed that are isogenic other than the presence of the triplication-containing LTR or mutations of it. Virus replication assays show that the triplication-containing LTR confers a distinct growth advantage on the virus, and implicate the 21-bp triplication in that function. Replacement of two copies of the triplicated element with a random sequence greatly diminishes the replicative capacity of the virus, thus implicating the triplicated sequence itself in LTR function. Our studies also indicate the binding of Myb transcription factor to a binding site formed at the junctions of the triplicated sequence. In addition to the unique triplication motif in the LTR, env sequence variation is also observed that is distinctive of FeLV proviruses in multicentric lymphomas. On the basis of the findings of this dissertation, we hypothesize that the interaction between the two viral genetic determinants, namely the LTR and env, can play a pivotal role/s in the malignant transformation of the appropriate target tissue