Abstract
Two mutants (BAYr1 and BAYr2) that are 100-fold and >3000-fold resistant, respectively, to the helicase-primase inhibitor (HPI) BAY 57-1293 were derived from a plaque-pure parental strain, HSV-1 SC16 cl-2. BAYr1 has two substitutions in the HSV-1 helicase (UL5) protein (A4 to V; K356 to Q) and BAYr2 has one (G352 to R). It was shown reproducibly that BAYr1 grows to higher titres in tissue culture while BAYr2 grows more slowly than wild-type. Marker transfer experiments confirmed that K356Q and G352R are the drug-resistance mutations and that they are directly associated with differences in virus growth in tissue culture. When BAYr1 was tested in a murine infection model, this virus was shown to be fully pathogenic. We present evidence that single mutations close to a predicted functional domain of an essential HSV-1 replication enzyme (helicase) are associated with drug resistance and virus growth characteristics.
Publication types
-
Research Support, Non-U.S. Gov't
MeSH terms
-
Amino Acid Sequence
-
Amino Acid Substitution*
-
Animals
-
Antiviral Agents / pharmacology
-
Chlorocebus aethiops
-
DNA Helicases / antagonists & inhibitors
-
DNA Helicases / genetics*
-
DNA Primase / antagonists & inhibitors
-
DNA Primase / genetics*
-
Drug Resistance, Viral / genetics*
-
Enzyme Inhibitors / pharmacology
-
Female
-
Herpes Simplex / mortality
-
Herpes Simplex / physiopathology
-
Herpes Simplex / virology
-
Herpesvirus 1, Human / drug effects
-
Herpesvirus 1, Human / enzymology
-
Herpesvirus 1, Human / genetics
-
Herpesvirus 1, Human / growth & development*
-
Herpesvirus 1, Human / pathogenicity
-
Humans
-
Mice
-
Mice, Inbred BALB C
-
Molecular Sequence Data
-
Pyridines / pharmacology
-
Sulfonamides
-
Thiazoles / pharmacology
-
Vero Cells
-
Viral Proteins / antagonists & inhibitors
-
Viral Proteins / genetics*
-
Virus Replication*
Substances
-
Antiviral Agents
-
Enzyme Inhibitors
-
Pyridines
-
Sulfonamides
-
Thiazoles
-
Viral Proteins
-
pritelivir
-
DNA Primase
-
helicase-primase, Human herpesvirus 1
-
DNA Helicases