Feline leukaemia virus LTR variation and disease association in a geographical and temporal cluster

Abstract

Feline leukaemia virus (FeLV)-945 was previously identified in natural multicentric lymphomas and contains a 21 bp tandem triplication in the LTR. In the present study, FeLV LTR variation was examined in the cohort from which FeLV-945 was identified. The objectives of the study were to evaluate FeLV LTR variation within the cohort, to determine whether the FeLV-945 LTR was associated uniquely with multicentric lymphoma and to evaluate functional attributes that may have contributed selective advantage to the predominant LTR variants observed. T-cell tumours uniformly contained LTRs with duplicated enhancer sequences, although enhancer duplications conferred little transcriptional advantage. Non-T-cell malignant, proliferative and degenerative diseases contained LTRs with two, three or four tandemly repeated copies of the 21 bp sequence originally identified in FeLV-945. While the length and termini of enhancer duplications were variable, the 21 bp repeat unit was invariant. Triplication of the 21 bp repeat conferred the optimal replicative advantage in feline cells.

Advances in understanding molecular determinants in FeLV pathology

“…It was striking that the sequence and position of the 21-bp triplication within the LTR was precisely conserved among independent isolates from the cohort (Prabhu et. al., 1999;Chandhasin et al, 2004). The SU protein of FeLV-945 was shown to be most closely related to natural horizontally-transmissible FeLV-A, but was observed to differ from an FeLV-A prototype to a greater extent than the known FeLV-A isolates differ among themselves Prabhu et al, 1999).…”

“…FeLV LTR sequence variation in the cohort was examined using PCR amplification and nucleotide sequence analysis. Specifically, genomic DNA from diseased tissues was amplified by PCR using primers specific for the U3 region of exogenous FeLV LTR (Prabhu et al, 1999;Chandhasin et al, 2004). Amplification products of multiple sizes were detected from most animals, indicating the presence of FeLV LTR sequence variation within the tissues of individuals.…”

“…LTRs containing 21-bp repeats were identified in seven of twelve multicentric lymphomas and in all cases of myeloproliferative disease and anemia. Unlike the enhancer duplications, the termini of the 21-bp repeat units were precisely conserved (Chandhasin et al, 2004). Functional studies were then initiated to establish the selective advantage responsible for the precise conservation of the 21-bp triplication in non-T-cell diseases in the cohort.…”

“…The LTR of FeLV, like that of other retroviruses, is a modular structure in which the U3 region contains the transcriptional promoter and enhancer elements required to direct gene expression. The LTR encodes the major determinant of tumorigenic potential and disease specificity of the gammaretroviruses, particularly within the repeat elements characteristic of the central enhancer motif (Fan, 1997;Chandhasin et al, 2004). The LTR of M-MuLV or FeLV, like other gammaretroviruses, is implicated in the malignant process in two ways: (1) by directing high levels of virus expression in relevant target tissues, and (2) by insertionally activating oncogenes at or near the sites of proviral integration.…”

“…We previously described a natural isolate of FeLV, termed FeLV-945, as the predominant species in a geographic and temporal cohort of naturally infected cats Chandhasin et al, 2004). The U3 region of the FeLV-945 LTR was shown to contain a unique repeat sequence motif, specifically, a single copy of the canonical transcriptional enhancer followed 25-bp downstream by the tandem triplication of a 21-bp repeat element.…”