Phenotypic Resistance of Herpes Simplex Virus Type 1 Strains Selected in Vitro with Antiviral Compounds and Combinations Thereof

Abstract

Several drug-resistant herpes simplex virus type 1 (HSV-1) strains were obtained under the selective pressure of various antiherpetic drugs used alone or in combination. Their susceptibility to a wide range of antiviral compounds was determined. Strains selected under the pressure of brivudin (BVDU) or 1-β-D-arabinofuranosyl-( E)-5-(2-bromovinyl)uracil (BVaraU) alone were composed of two virus populations: (1) virus resistant to BVDU and BVaraU but not to acyclovir (ACV) or ganciclovir (GCV), which is suggestive of an alteration in the thymidylate kinase activity associated with the viral thymidine kinase (TK) (responsible for the phosphorylation of BVDU-monophosphate to BVDU-diphosphate); and (2) virus resistant to BVDU, BVaraU, ACV and GCV, which is indicative of an alteration in the viral TK activity that converts BVDU, BVaraU and other nucleoside analogues such as ACV and GCV to their monophosphate derivatives. Strains resistant to TK-dependent drugs (i.e. ACV, GCV, BVDU and BVaraU) as well as double-mutant strains with decreased sensitivity to both TK-dependent compounds and the pyrophosphate analogues foscarnet (PFA) and phosphonoacetic acid (PAA) (suggestive of mutations at the level of the DNA polymerase) were recovered under the selective pressure of ACV alone or in combination with BVDU or BVaraU. Combinations of BVDU or BVaraU with PFA or PAA led to strains resistant only to BVDU and BVaraU or double-mutant strains resistant to BVDU, BVaraU and the pyrophosphate analogues, but not to strains resistant to other TK-dependent drugs. Interestingly, strains resistant to ACV, BVDU, GCV and/or the pyrophosphate analogues PFA and PAA remained sensitive to the (S)-3-hydroxy-2-phosphonylmethoxypropyl (HPMP) derivatives of cytosine (HPMPC) and adenine (HPMPA).