First clinical description of letermovir resistance mutation in cytomegalovirus UL51 gene and potential impact on the terminase complex structure

Immunovirology of cytomegalovirus infection in allogeneic stem cell transplant recipients undergoing prophylaxis with letermovir: A narrative review

“…[88][89][90][91][92]102 Single mutations leading to LMV resistance were individually characterized by recombinant phenotyping, showing different degrees of resistance, ranging from <4 to >3000-fold changes in EC 50 (Supporting Information: Table S1). [88][89][90][91][92][93]95,[98][99][100]103 Of note, viral replicative fitness was preserved in most mutants, as demonstrated by viral growth curves. [89][90][91][92] Interestingly, mutations within the UL56 gene arose at low LMV concentrations (1.4-fold EC 50 ), suggesting a low genetic barrier to resistance 89 ; however, pUL56 virus mutants arising at low LMV concentrations (F261L) exhibited a low to medium level of resistance (4-15-fold change in LMV EC 50 ), whereas amino acid substitutions conferring >1000-fold change in LMV EC 50 , such as C325F/R or M329T, were predominantly selected at much higher LMV concentrations (>1 µM).…”

“…LMV-resistant CMV mutants arising in vivo, during LMV treatment, have been reported. [93][94][95][96][97][98][99][100][101]104 Data from the Phase II and III LMV prophylaxis clinical trials revealed that, overall, the emergence incidence of LMV resistance was very low. Genotyping results showed that two mutations in pUL56, V236M, and C325W, known to be associated with high LMV-resistance levels, were predominantly selected in vivo.…”

“…Most of these mutations map within the highly conserved region (between codons 229 and 369) of the UL56 gene, and less frequently within UL89 and UL51 (Table 3). 88–92,102 Single mutations leading to LMV resistance were individually characterized by recombinant phenotyping, showing different degrees of resistance, ranging from <4 to >3000‐fold changes in EC 50 (Supporting Information: Table ) 88–93,95,98–100,103 . Of note, viral replicative fitness was preserved in most mutants, as demonstrated by viral growth curves 89–92 .…”

“…LMV‐resistant CMV mutants arising in vivo, during LMV treatment, have been reported 93–101,104 . Data from the Phase II and III LMV prophylaxis clinical trials revealed that, overall, the emergence incidence of LMV resistance was very low.…”

“…Using Sanger and NGS sequencing, Muller et al, 100 analyzed a total of 16 samples from patients with active CMV infection who received LMV (either as prophylaxis or PET) and compared their UL56 / UL89 / UL51 sequences with those obtained from 56 LMV‐naïve samples and reference CMV strains. The authors found a novel substitution in a very conserved region of the C‐terminus of pUL51 (A95V), which was associated with resistance to LMV (13.8‐fold change in EC 50 alone and 127.8‐fold in combination with L257I in UL56 ).…”