Mutations close to functional motif IV in HSV-1 UL5 helicase that confer resistance to HSV helicase-primase inhibitors, variously affect virus growth rate and pathogenicity.
Herpes simplex virus (HSV) helicase-primase (HP) is the target for a novel class of antiviral compounds, the helicase-primase inhibitors (HPIs), e.g. BAY 57-1293. Although mutations in herpesviruses conferring resistance to nucleoside analogues are commonly associated with attenuation in vivo, to date, this is not necessarily true for HPIs. HPI-resistant HSV mutants selected in tissue culture are reported to be equally pathogenic compared to parental virus in animal models. Here we demonstrate that a slow-growing HSV-1 mutant, with the BAY 57-1293-resistance mutation Gly352Arg in UL5 helicase, is clearly less virulent than its wild-type parent in a murine zosteriform infection model. This contrasts with published results obtained for a mutant containing a different HPI-resistance substitution (Gly352Val) at the same location, since this mutant was reported to be fully pathogenic. We believe our report to be the first to describe an HPI-resistant HSV-1 mutant, that is markedly less virulent in vivo and slowly growing in tissue culture compared to the parental strain. Another BAY 57-1293-resistant UL5 mutant (Lys356Gln), which showed faster growth characteristics in cell culture, however, was at least equally virulent compared to the parent strain.
Biswas
Subhajit
S
Department of Veterinary Medicine, University of Cambridge, Cambridge, United Kingdom. sb507@cam.ac.uk
Tiley
Laurence S
LS
Zimmermann
Holger
H
Birkmann
Alexander
A
Field
Hugh J
HJ
D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology; D002522:Chlorocebus aethiops; D004265:DNA Helicases / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000235:genetics*; D019915:DNA Primase / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000235:genetics*; D024882:Drug Resistance, Viral / Q000235:genetics*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006561:Herpes Simplex / Q000473:pathology / Q000821:virology; D018259:Herpesvirus 1, Human / Q000187:drug effects / Q000235:genetics / Q000254:growth & development / Q000472:pathogenicity; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D009154:Mutation; D011725:Pyridines / Q000494:pharmacology; D013449:Sulfonamides; D013844:Thiazoles / Q000494:pharmacology; D014709:Vero Cells; D014764:Viral Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000235:genetics*; D014774:Virulence
D000998:Antiviral Agents; D004791:Enzyme Inhibitors; D011725:Pyridines; D013449:Sulfonamides; D013844:Thiazoles; D014764:Viral Proteins; C453221:pritelivir; D019915:DNA Primase; C062021:helicase-primase, Human herpesvirus 1; D004265:DNA Helicases