DNA polymerase mutations in drug-resistant herpes simplex virus mutants determine in vivo neurovirulence and drug-enzyme interactions

Antivir Ther. 2007;12(5):719-32.


Mutations in the thymidine kinase and DNA polymerase genes of herpes simplex virus (HSV) might confer resistance to antiviral drugs, particularly in immunocompromised patients who suffer from chronic and/or disseminated lesions. The patterns of cross-resistance and neurovirulence in mice of several DNA polymerase mutants selected under pressure of foscarnet (PFA) and different acyclic nucleoside phosphonates (ANPs), including (S)-3-hydroxy-2-phosphonylmethoxypropyl (HPMP) derivatives of adenine (HPMPA) and cytosine (HPMPC, cidofovir) and 2-phosphonylmethoxyethyl (PME) derivatives of adenine (PMEA) and 2,6-diaminopurine (PMEDAP), were investigated. The mutants were derived from the HSV-1 strain KOS following either single or multiple steps of selection with PFA (V714M, A719V, 5724N and T821M), PMEA (S724N, L802F and R959H), PMEDAP (Q618H, S724N, S724N+D1070N), HPMPC (V573M, R700M and K960R) or HPMPA (W998L, L1007M and 11028T). These amino acid substitutions were located in different subdomains of the HSV-1 DNA polymerase, either in conserved or non-conserved regions. The sensitivity of the mutants to a new class of ANPs, the 6-(2-[phosphonomethoxy]alkoxy)pyrimidines HPMPO-DAPy and PMEO-DAPy, was investigated. Cross-resistance between the HPMP derivatives and HPMPO-DAPy, on the one hand, and between the PME derivatives and PMEO-DAPy, on the other hand, was observed. Different degrees of cross-resistance between PME derivatives, PMEO-DAPy, PFA and acyclovir were noticed. The mutants ranged from exhibiting near wild-type neurovirulence (V714M, A719V, 5724N and L1007M) to significant attenuation (Q618H, S724N+D1070N, L802F, R700M, K960R, W998L and 11028T) or higher levels of attenuation (V573M). It appears that drug-resistant mutants arising under the pressure of HPMP derivatives have the lowest levels of neurovirulence.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenine / analogs & derivatives
  • Adenine / pharmacology
  • Animals
  • Antiviral Agents / metabolism
  • Antiviral Agents / pharmacology*
  • Antiviral Agents / therapeutic use
  • Chlorocebus aethiops
  • Cidofovir
  • Cytosine / analogs & derivatives
  • Cytosine / pharmacology
  • DNA-Directed DNA Polymerase / chemistry
  • DNA-Directed DNA Polymerase / genetics
  • DNA-Directed DNA Polymerase / metabolism
  • Disease Models, Animal
  • Drug Resistance, Multiple, Viral / genetics*
  • Enzyme Inhibitors / metabolism
  • Enzyme Inhibitors / pharmacology*
  • Enzyme Inhibitors / therapeutic use
  • Exodeoxyribonucleases / antagonists & inhibitors*
  • Exodeoxyribonucleases / chemistry
  • Exodeoxyribonucleases / genetics
  • Exodeoxyribonucleases / metabolism
  • Foscarnet / pharmacology
  • Genotype
  • Herpes Simplex / drug therapy*
  • Herpes Simplex / enzymology
  • Herpes Simplex / virology
  • Herpesvirus 1, Human / drug effects*
  • Herpesvirus 1, Human / enzymology
  • Herpesvirus 1, Human / genetics
  • Herpesvirus 1, Human / pathogenicity
  • Humans
  • Mice
  • Models, Molecular
  • Mutation*
  • Nucleic Acid Synthesis Inhibitors*
  • Organophosphonates / pharmacology
  • Phenotype
  • Protein Binding
  • Protein Conformation
  • Vero Cells
  • Viral Proteins / antagonists & inhibitors*
  • Viral Proteins / chemistry
  • Viral Proteins / genetics
  • Viral Proteins / metabolism
  • Virulence / genetics


  • Antiviral Agents
  • Enzyme Inhibitors
  • Nucleic Acid Synthesis Inhibitors
  • Organophosphonates
  • Viral Proteins
  • Foscarnet
  • 9-(2-phosphonylmethoxyethyl)-2,6-diaminopurine
  • adefovir
  • Cytosine
  • 9-(S)-(3-hydroxy-2-(phosphonomethoxy)propyl)adenine
  • DNA-Directed DNA Polymerase
  • Exodeoxyribonucleases
  • DNA polymerase, Simplexvirus
  • Adenine
  • Cidofovir