title: DNA polymerase mutations in drug-resistant herpes simplex virus mutants determine in vivo neurovirulence and drug-enzyme interactions.
abstract: 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.
authors: Laboratory of Virology, Rega Institute for Medical Research, K U Leuven, Belgium. graciela.andrei@rega.kuleuven.ac.be
authors: Gracíela
authors: G
authors: Andrei
authors: Pierre
authors: P
authors: Fiten
authors: Matheus
authors: M
authors: Froeyen
authors: Erik
authors: E
authors: De Clercq
authors: Ghislain
authors: G
authors: Opdenakker
authors: Robert
authors: R
authors: Snoeck
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D000998:Antiviral Agents / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D002522:Chlorocebus aethiops; D000077404:Cidofovir; D003596:Cytosine / Q000031:analogs & derivatives / Q000494:pharmacology; D004259:DNA-Directed DNA Polymerase / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D024921:Drug Resistance, Multiple, Viral / Q000235:genetics*; D004791:Enzyme Inhibitors / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D005090:Exodeoxyribonucleases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D017245:Foscarnet / Q000494:pharmacology; D005838:Genotype; D006561:Herpes Simplex / Q000188:drug therapy* / Q000201:enzymology / Q000821:virology; D018259:Herpesvirus 1, Human / Q000187:drug effects* / Q000201:enzymology / Q000235:genetics / Q000472:pathogenicity; D006801:Humans; D051379:Mice; D008958:Models, Molecular; D009154:Mutation; D019384:Nucleic Acid Synthesis Inhibitors; D063065:Organophosphonates / Q000494:pharmacology; D010641:Phenotype; D011485:Protein Binding; D011487:Protein Conformation; D014709:Vero Cells; D014764:Viral Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D014774:Virulence / Q000235:genetics
chemical_list: D000998:Antiviral Agents; D004791:Enzyme Inhibitors; D019384:Nucleic Acid Synthesis Inhibitors; D063065:Organophosphonates; D014764:Viral Proteins; D017245:Foscarnet; C059499:9-(2-phosphonylmethoxyethyl)-2,6-diaminopurine; C053001:adefovir; D003596:Cytosine; C050127:9-(S)-(3-hydroxy-2-(phosphonomethoxy)propyl)adenine; D004259:DNA-Directed DNA Polymerase; D005090:Exodeoxyribonucleases; C043417:DNA polymerase, Simplexvirus; D000225:Adenine; D000077404:Cidofovir