Genetic variants of the TbAT1 adenosine transporter from African trypanosomes in relapse infections following melarsoprol therapy

We have analyzed the TbAT1 genie, which codes for the P2 adenosine transpor ter, from Trypanosoma brucei field isolates to investigate a possible link between the presence of mutations in this gene and melarsoprol treatment fa ilure. Of 65 T. b. gambiense isolates analyzed from a focus in north-wester n Uganda with high treatment failure rates following melarsoprol therapy, 3 8 had a mutated TbAT1. Unexpectedly, all individual isolates contained the same set of nine mutations in their TbAT1 genes. Of these, five point mutat ions resulted in amino acid substitutions, one resulted in the deletion of an entire codon, and three were silent point mutations. Eight of these muta tions had previously been reported in a laboratory-derived Cymelarsan-resis tant T. b. brucei clone. Identical sets of mutations were also found in a d rug-resistant T.b.rhodesiense isolate from south-eastern Uganda and in a T. b.gambiense isolate from a relapsing patient from northern Angola. A deleti on of the TbAT1 gene was found in a single T. b. gambiense isolate from a r elapsing patient from northern Angola. The data presented demonstrate the s urprising finding that trypanosomes from individual relapse patients of one area, as well as from geographically distant localities, contain an identi cal set of point mutations in the transporter gene TbAT1. They further demo nstrate that many isolates from relapse patients contained the wild-type Tb AT1 genes, suggesting that melarsoprol refractoriness is not solely due to a mutational inactivation of TbAT1. (C) 2001 Elsevier Science B.V. All righ ts reserved.