The Development of Drug Resistance in HSV-1 to Helicase-primase Inhibitors

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The Development of Drug Resistance in HSV-1 to Helicase-primase Inhibitors

Hugh J Field
Department of Veterinary Medicine, University of Cambridge, Madingley Road, Cambridge, CB3 0ES. hjf10@cam.ac.uk

Helicase primase inhibitors (HPI) represent a new class of highly potent herpes simplex virus (HSV) antivirals and several are currently in clinical development. The efficacy of one (BAY 57-1293) was confirmed in a murine infection model for HSV-1. The compound once per day was extremely effective in both normal and immunompromised mice comparing favourably with famciclovir. A claimed advantage of HPI is their low selection of resistance (=10-6). Surprisingly, we found 100 times higher frequencies of resistance (10-4) in two laboratory strains of HSV, although the rates reduced to approx. to 10-6 in plaque-pure derivatives. The same parental viruses and plaque-pure derivatives however, showed no difference in the frequency of acyclovir-resistant variants. The majority of BAY 57-1293-resistant variants contained single base substitutions in the helicase gene, UL5. A panel of ten recent clinical isolates were examined. All were sensitive to HPI within the normal range, however two were found to contain high levels of BAY 57-1293-resistant variants. It was of interest that both clinical isolates (from unrelated patients) yielded the same single resistance mutation in UL5. The implications of these finding will be discussed.

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Last Updated : 04/12/2007 12:30:09