Progressive Esophagitis from Acyclovir-Resistant Herpes Simplex: Clinical Roles for DNA Polymerase Mutants and Viral Heterogeneity?
ABSTRACT Clinically acquired acyclovir resistance in herpes simplex has usually been associated with a deficiency in viral thymidine kinase, which, in turn, has been linked with attenuated virulence in animal models. Diminished pathogenicity in thymidine kinase-deficient isolates has been partly responsible for controversies about the clinical significance of antiviral resistance. We report on a series of resistant virus isolates from a patient who had severe, progressive esophagitis. These isolates had various thymidine kinase activities, ranging from 2.8% to 130% when compared with the activity of the isolate obtained before treatment; the resistant isolate 615 retained enzyme activity as well as neurovirulence in an encephalitis model. Plaque purification showed a heterogeneous mixture containing at least one acyclovir-resistant, foscarnet-resistant plaque isolate (615.8) fully able to phosphorylate acyclovir. The 3.3-kbp BamHI fragment containing most of the DNA polymerase gene from isolate 615.8 was purified and used to successfully transfer both acyclovir and foscarnet resistance. Acquisition of in-vitro acyclovir resistance was associated with progression of clinical disease, as well as with maintenance of pathogenicity in an animal model and at least one mutation in viral DNA polymerase. Patients with herpes simplex infections that progress during acyclovir therapy should be observed for acquisition of resistance in the setting of antiviral chemotherapy; future studies should also consider the presence of heterogeneous virus populations in such patients.
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ABSTRACT: Some of the most successful antiviral agents currently available are effective against herpes simplex virus. However, resistance to these drugs is frequently associated with significant morbidity, particularly in immunocompromised patients. In addition to the clinical implications of drug resistance, the range of biological processes exploited by the virus to attain resistance while maintaining pathogenicity is proving to be surprising. These mechanisms, which include ribosomal frameshifting, induced infidelity of the DNA polymerase, and internal ribosome entry, are discussed.Drug resistance updates: reviews and commentaries in antimicrobial and anticancer chemotherapy 09/2011; 14(6):251-9. DOI:10.1016/j.drup.2011.08.003 · 8.82 Impact Factor
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ABSTRACT: Herpes simplex virus can infect the mammalian brain causing lethal encephalitis (neurovirulence). Previously, herpes simplex virus mutants that are attenuated for neurovirulence have exhibited defects in replication in brain and/or blocks to replication in neuronal cells. We investigated the attenuation of neurovirulence of mutant PAAr5, which exhibits resistance to antiviral drugs due to altered viral DNA polymerase. Following intracerebral inoculation of 7-week-old CD1 mice, PAAr5 was 30-fold attenuated for neurovirulence compared to its wild-type parent. A drug-sensitive virus derived by marker rescue with DNA polymerase gene sequences exhibited neurovirulence that was essentially indistinguishable from that of wild-type virus, demonstrating that attenuation was due to a polymerase mutation. PAAr5 replicated in brain similarly to wild-type virus unlike another polymerase mutant, 615.8, that exhibited a similar degree of attenuation. The attenuation of PAAr5 was not associated with altered particle to PFU ratios nor with any obvious reductions in viral antigen expression in neurons, spread, histopathology, or TUNEL staining suggestive of apoptotic cells. Thus PAAr5 differs from other mutants that are attenuated for neurovirulence. Understanding how a polymerase mutation specifically attenuates neurovirulence may shed light on how herpes simplex virus can cause lethal encephalitis.Virology 01/1999; 252(2):364-72. DOI:10.1006/viro.1998.9447 · 3.28 Impact Factor
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ABSTRACT: The Herpes simplex Virus (HSV) resistance to acyclovir (ACV) occurs in a 5% of the inmunocompromised patients, approximately. The treatment with analogs of nucleosides, causes the appearance of resistent HSV-ACV stocks (ACVr) which can be produced by alteration in genes coding for the TK or the DNA-polymerase. A previous large-scale clinical study on ACVr HSV strains isolated from patients infected with human immunodeficiency virus indicated that 96% of ACVr HSV mutants were low producers of, or deficient in, TK activity (TK-), with 4% being TK mutants with an altered substrate specificity. No DNA Pol mutants were isolated. The pirophosphate analogs generate resistance in the gene of DNA-polymerase by mutation. In this paper we show the methodology used for the determination of sensibilite profiles to ACV and Phoscarnet (PFA) in a population of inmunocompromised patients. We analized 46 HSV strain from vesicular injuries of transplanted patients. All samples, were inoculated in human fibroblasts and the HSV isolates were identified by inmunofluorescence whith monoclonal antibodies. These strains were amplified and the profile of susceptibility determinated in Vero cells, using 100 tissue culture inhibition dosis 50 (TCID50) of each Viral stock and the specific antiviral drugs in different concentrations. The cytopathic effect (CPE) was evaluated after 72hs. post infection. The 50% inhibitory concentration (CI50) was calculated from the percentage of inhibition of the ECP based on the concentration of the drug. From 46 isolations, 26 were HSV-1 and 20 were HSV-2. Two of them, one HSV-1 and one HSV-2, were resistant to ACV and none of the isolates were resistant to PFA.Revista Argentina de microbiología 01/2004; 36(2):88-91. · 0.66 Impact Factor