Novel mutation (A427S) in the CMV UL97 gene associated with resistance to ganciclovir
Abstract number: P548
Anton A., Dimova V., Pumarola T., Cervera C., Linares L., Moreno A., Cofan F., Jimenez de Anta M.T., Marcos M.A.
Introduction: Cytomegalovirus (CMV) infection is the leading viral cause of morbidity and mortality in kidney transplant recipients. Mutations in the CMV UL97 gene product, which confer ganciclovir (GCV) resistance, are well known but some unusual sequence changes observed in specimens from treated subjects remain uncharacterised.
Patient and Methods: We report a male who underwent a kidney transplant (D+/R+) and where we detected on posttransplant day 111 a CMV resistant strain to GCV, after treatment for 5 weeks. The patient was monitored for CMV infection after transplantation by CMV antigenaemia and viral load. When antiviral resistance was suspected, mutation screening by PCR sequencing of CMV UL97 and UL54 was performed from plasma samples. The amplified regions included almost all of the known resistance mutations. Derived sequences of each isolate were aligned with the strain AD169 reference sequence and amino acid differences were compared with previously published.
Results and Conclusions: Nucleotide sequence of the UL54 and UL97 of the clinical isolate showed 5 amino acid substitutions (N685S, S655L, N898D, S897L and A885T) in UL54, which were polymorphisms as already described, and 5 mutations (A427S, C428M, I429H, D430A, Y432N) in UL97. To our knowledge these mutations in UL97 of unknown significance have not been described yet. The codon 427 is outside the region with well-known mutations (codons 460, 520, and 590607) related to GCV resistance. A change in the codon 427 (A427V) was already reported and phenotyped in a BAC recombination system as GCV sensitive (Martin M et al, 2006). In case we had been able to isolate this strain, the sensitivity test to GCV by phenotyping assay would have been interesting. As we did not detect these UL97 mutations from samples collected just in the beginning of the GCV treatment, we think that these may be associated with resistance to GCV. The antiviral treatment in this patient was changed to foscarnet with good virological response. Definitive conclusions about the role that such mutations play would require a marker transfer of the mutated UL97 region in a known susceptible CMV strain and the corresponding IC50 value by recombinant phenotyping to know their role in drug resistance.
|Session name:||19th European Congress of Clinical Microbiology and Infectious Diseases|
|Location:||Helsinki, Finland, 16 - 19 May 2009|
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