Progressive Esophagitis from Acyclovir-Resistant Herpes Simplex: Clinical Roles for DNA Polymerase Mutants and Viral Heterogeneity?

University of British Columbia, Vancouver.
Annals of internal medicine (Impact Factor: 17.81). 01/1990; 111(11):893-9. DOI: 10.7326/0003-4819-111-11-893
Source: PubMed


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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    • "Cells, viruses, and mice Vero cells were maintained and propagated according to American Type Culture Collection instructions. Wild-type HSV-1 strains KOS, RE, 294.1 (Sacks et al., 1989), and McKrae were propagated and titrated on Vero cell monolayers. C57BL/6, BALB/c, and ICR mice were obtained from The Jackson Laboratory (Bar Harbor, ME) and maintained in the laboratory animal center of our college. "
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    ABSTRACT: The majority of encephalitis induced by herpes simplex virus type I (HSV-1) is due to viral reactivation from latency, but few studies have investigated the factors influencing viral reactivation in the brain due to the lack of a sensitive assay. We have established an ex vivo explant assay, which induced efficient viral reactivation in the dissociated mouse brain. Applying this assay, we investigated the infection of four HSV-1 strains with varying degrees of neurovirulence in three mouse strains with different levels of susceptibility to HSV-1 infection. We found that virulent HSV-1 strains and susceptible mouse strains exhibited prolonged viral growth during acute infection, increased latent viral genomes, and efficient explant reactivation in the brain stem. Collectively, both viral neurovirulence and host susceptibility positively correlate with HSV-1 reactivation from the explanted mouse brain.
    Virology 08/2012; 433(1):116-23. DOI:10.1016/j.virol.2012.07.018 · 3.32 Impact Factor
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    • "Indeed, it is likely that the true extent of heterogeneity in clinical isolates is poorly understood; the latest massively parallel sequencing technologies will allow detailed genotypic analyses of drug-resistant HSV isolates. To date, the most informative reports of clinically relevant heterogeneity have derived from a series of isolates from a bone marrow transplant patient who developed severe, progressive herpetic esophagitis despite systemic ACV treatment (Sacks et al., 1989). One HSV-1 sample taken at 36 days post-transplant was ACV r and foscarnet 1 resistant . "
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    • "Vero cells were propagated as described (Weller et al., 1983). Viruses used in this study were wt HSV-1 strain KOS and, derived from KOS, pol mutant PAA r 5 (Jofre et al., 1977) and recombinant virus, P5Aph ϩ K2 (Coen et al., 1983); and clinical isolate HSV-1 strain 294 and the pol mutant derived from it, 615.8 (Sacks et al., 1989). Viruses were propagated and titered as described (Coen et al., 1985) except that high-titer stocks were prepared by pelleting infected cells by low-speed centrifugation and resuspending them in ϳ1/10th the volume of the supernatant prior to freezing, thawing, and sonication. "
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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.
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