Effects of therapy using a helicase-primase inhibitor (HPI) in mice infected with deliberate mixtures of wild-type HSV-1 and an HPI-resistant UL5 mutant.
Point mutations in the HSV-1 UL5 (helicase) gene confer resistance to helicase-primase inhibitors (HPIs), e.g. BAY 57-1293. Such mutations normally occur at a frequency of < or =10(-6)PFU. However, individual HSV-1 laboratory strains and some clinical isolates contained resistance mutations (e.g. UL5: Lys356Asn) at 10(-4)PFU. To address the possibility that pre-existing mutants at high frequency might have an impact on therapy using HPIs, deliberate mixtures were prepared to contain the SC16 UL5: Lys356Asn mutant in SC16 wild-type in the proportion of 1/500 or 1/50PFU. Mice were infected in the neck-skin with 5x10(4)PFU/mouse of wt alone, mutant alone, or the respective mixture. The mutant could not be detected in infectious virus yields from mice inoculated with the 1/500 mixture. However, resistant mutant was recovered from some treated mice inoculated with the 1/50 mixture. All mice inoculated with mixtures remained responsive to BAY 57-1293-therapy with no increase in clinical signs compared to treatment of wt-infected mice.
Sukla
Soumi
S
Department of Veterinary Medicine, University of Cambridge, United Kingdom.
Biswas
Subhajit
S
Birkmann
Alexander
A
Lischka
Peter
P
Ruebsamen-Schaeff
Helga
H
Zimmermann
Holger
H
Field
Hugh J
HJ
D019943:Amino Acid Substitution / Q000235:genetics; D000818:Animals; D000998:Antiviral Agents / Q000627:therapeutic use*; D004265:DNA Helicases / Q000037:antagonists & inhibitors* / Q000235:genetics; D019915:DNA Primase / Q000037:antagonists & inhibitors* / Q000235:genetics; D024882:Drug Resistance, Viral; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D005260:Female; D006561:Herpes Simplex / Q000188:drug therapy* / Q000821:virology; D018259:Herpesvirus 1, Human / Q000187:drug effects* / Q000201:enzymology / Q000235:genetics; D051379:Mice; D008807:Mice, Inbred BALB C; D020125:Mutation, Missense; D016896:Treatment Outcome; D014764:Viral Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics
D000998:Antiviral Agents; D004791:Enzyme Inhibitors; D014764:Viral Proteins; D019915:DNA Primase; C062021:helicase-primase, Human herpesvirus 1; D004265:DNA Helicases