High Frequency of Spontaneous Helicase-Primase Inhibitor (BAY 57–1293) Drug-Resistant Variants in Certain Laboratory Isolates of HSV-1

Abstract

The authors wish to draw attention to the following errors in their article: On page 15 an incorrect sequence database was referenced. The sentence ‘A set of eight pairs of overlapping HSV-1-specific primers (designed on the basis of HSV-1 strain 17 sequence; Genbank accession number NC001806) was used (McGeoch et al., 1988).’ should read ‘A set of eight pairs of overlapping HSV-1-specific primers (designed on the basis of HSV-1 strain 17 sequence; RefSeq accession number NC001806) was used (McGeoch et al., 1988).’ On Table 2 an incorrect symbol was used: ‘$reported by Liuzzi et al., 2004’ should be replaced by ‘♠reported by Liuzzi et al., 2004’. A corrected table can be found below. On Table 3 the 5th column heading is incorrect: ‘BAY 57–1293 concentration, mg/ml’ should read ‘BAY 57–1293 concentration µg/ml’. A corrected table can be found below. Table 2.Observed frequency of BAY 57-1293 and other HPI-resistant variants in various laboratory isolates of HSV-1 and mutations in the helicase (UL5) protein *Frequency expressed as observed number of drug-resistant plaque-forming units (PFU) in the total number of PFU screened; †reported by Kleymann et al., 2002; ‡SC16 crude stock reproducibly contained >10× more drug-resistant variants than that observed for plaque-purified SC16 cl-2; §novel substitutions, not previously reported as BAY 57-1293-resistant mutations; ¶PDK crude stock reproducibly contained >70 × more drug-resistant variants than that observed for plaque-purified PDK cl-1; ♠reported by Liuzzi et al., 2004; $reported by Spector et al., 1998. Bold type indicates the BAY 57-1293-resistant variants occurring at high frequency and the corresponding laboratory isolates in which they were detected. ED50, 50% effective dose; HPI, helicase-primase inhibitor; HSV, herpes simplex virus; n/s, not specified. Table 3.A summary of BAY 57-1293-resistant variants showing the methods used for their selection Fifty percent effective dose (ED50)data was determined by plaque reduction assay in Vero cells and was significantly different from respective wild-type in an un-paired 2-tailed t-test (P<0.001). *From Figure 6A; †from Figure 6B; ‡from Figure 6C; §from Figure 6D.

The Novel Anticytomegalovirus Compound AIC246 (Letermovir) Inhibits Human Cytomegalovirus Replication through a Specific Antiviral Mechanism That Involves the Viral Terminase

“…Drug-resistant HCMV AD169 mutants were selected by the single-step selection method (5,12). Briefly, 5 ϫ 10 3 AD169-infected NHDF cells/well (MOI, 0.03 PFU/cell) were seeded into the wells of 30 96-well microtiter plates.…”

Inhibition of clinical pathogenic herpes simplex virus 1 strains with enzymatically created siRNA pools

“…Another concern is the frequency of emergence of drug resistant viruses due to mutations in the siRNA target site in the viral genome [Shah et al, ; McDonagh et al, ]. Furthermore, in the case of HSV, pre‐existing viral genomic diversity is a source of drug resistance that challenges effective drug development [Biswas et al, ; Sukla et al, ]. To address these issues, enzymatically created siRNA pools were designed that cover hundreds of nucleotides of the viral target genome, thus rendering resistance against all the siRNAs by mutation unlikely.…”

Anti‐DNAVirus Agents

“…Several spontaneous helicase/primase-drug-resistant variants have been detected, which were resistant to BAY 57-1293 and cross-resistant to BILS 22BS, and which did not revert to the sensitive phenotype in the absence of the inhibitor [155].…”