Fulminant, Acyclovir-Resistant, Herpes Simplex Virus Type 2 Hepatitis in an Immunocompetent Woman

Czartoski, Todd; Liu, Charlie; Koelle, David M.; Schmechel, Stephen C.; Kalus, Andrea; Wald, Anna

doi:10.1128/jcm.44.4.1584-1586.2006

Cited by 52 publications

(34 citation statements)

References 25 publications

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“…The mutation seemed to disrupt the three-dimensional structure of the whole active site by shifting the LID domain, resulting in a more open catalytic active conformation (129). Mutations were also located in conserved site 2 (78,150,182) and site 6 (66,98,113). In addition, several mutations were also shown to confer resistance to ACV despite their location outside highly conserved regions of the UL23 gene (28,44,78,98,125,150,214,223).…”

Section: Mechanism Of Resistance To Nucleoside Analoguesmentioning

confidence: 99%

“…In general, in this population, drug resistance was not associated with an adverse clinical outcome, due to immune competence. Cases of HSV resistance reported in immunocompetent patients were associated with diagnosis of recurrent genital herpes (81,109,125,126,153,219), keratitis (156,188), disseminated HSV infection (66), and encephalitis (197). Recently, a report documented a relatively high (6.4%) prevalence of ACV-resistant HSV-1 isolates in immunocompetent patients with herpes keratitis, and some of these cases were clinically refractory to ACV therapy (77).…”

Section: Prevalence Of Drug-resistant Hsvmentioning

confidence: 99%

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Resistance of Herpes Simplex Viruses to Nucleoside Analogues: Mechanisms, Prevalence, and Management

Piret

Boivin

2011

Antimicrob Agents Chemother

473

406

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Section: Mechanism Of Resistance To Nucleoside Analoguesmentioning

confidence: 99%

Section: Prevalence Of Drug-resistant Hsvmentioning

confidence: 99%

Resistance of Herpes Simplex Viruses to Nucleoside Analogues: Mechanisms, Prevalence, and Management

Piret

Boivin

2011

Antimicrob Agents Chemother

473

406

View full text Add to dashboard Cite

“…In contrast, TK activity is important for virus replication in resting cells or neurons (22,38). Though Acv r HSV infection rarely has clinical significance in immunocompetent individuals (7,15,24,27,37), severe disease can occur in immunocompromised persons such as AIDS patients and bone marrow transplant recipients (29,40).The majority (Ͼ95%) of Acv r clinical isolates from human skin lesions have mutations in the viral tk gene, while the remainder have mutations in the viral DNA polymerase gene (2,9,29). A vast array of mutations in the HSV tk gene affect TK activity.…”

mentioning

confidence: 99%

Diverse Herpes Simplex Virus Type 1 Thymidine Kinase Mutants in Individual Human Neurons and Ganglia

Wang¹,

Mahalingam²,

Hoover³

et al. 2007

J Virol

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Mutations in the thymidine kinase gene (tk) of herpes simplex virus type 1 (HSV-1) explain most cases of virus resistance to acyclovir (ACV) treatment. Mucocutaneous lesions of patients with ACV resistance contain mixed populations of tk mutant and wild-type virus. However, it is unknown whether human ganglia also contain mixed populations since the replication of HSV tk mutants in animal neurons is impaired. Here we report the detection of mutated HSV tk sequences in human ganglia. Trigeminal and dorsal root ganglia were obtained at autopsy from an immunocompromised woman with chronic mucocutaneous infection with ACV-resistant HSV-1. The HSV-1 tk open reading frames from ganglia were amplified by PCR, cloned, and sequenced. tk mutations were detected in a seven-G homopolymer region in 11 of 12 ganglia tested, with clonal frequencies ranging from 4.2 to 76% HSV-1 tk mutants per ganglion. In 8 of 11 ganglia, the mutations were heterogeneous, varying from a deletion of one G to an insertion of one to three G residues, with the two-G insertion being the most common. Each ganglion had its own pattern of mutant populations. When individual neurons from one ganglion were analyzed by laser capture microdissection and PCR, 6 of 14 HSV-1-positive neurons were coinfected with HSV tk mutants and wild-type virus, 4 of 14 were infected with wild-type virus alone, and 4 of 14 were infected with tk mutant virus alone. These data suggest that diverse tk mutants arise independently under drug selection and establish latency in human sensory ganglia alone or together with wild-type virus.The deoxyguanosine homolog acyclovir (ACV) is the most common drug used to treat herpes simplex virus (HSV) infections. After being taken up into cells, ACV is sequentially converted into ACV monophosphate, ACV diphosphate, and finally its active form, ACV triphosphate. The first step of the sequential phosphorylations requires HSV-encoded thymidine kinase (TK); however, cellular enzymes perform the additional phosphorylations. ACV triphosphate is more efficiently incorporated into replicating DNA by HSV DNA polymerase than by the cellular DNA polymerase (8). These characteristics of ACV result in its selectivity for virus-infected cells and its extremely low toxicity to uninfected cells. However, if HSV loses its TK function (including an alteration in substrate specificity or the loss of TK activity) or its DNA polymerase has altered substrate affinity, the virus becomes ACV resistant (Acv r ). While viral TK function is crucial for ACV activity, TK is not essential for HSV to replicate in dividing cells (22) such as human epithelial cells, presumably due to the abundance of nucleotides in these cells. Thus, a TK Ϫ HSV mutant that is resistant to ACV therapy can still replicate in epithelial cells and cause lesions. In contrast, TK activity is important for virus replication in resting cells or neurons (22,38). Though Acv r HSV infection rarely has clinical significance in immunocompetent individuals (7,15,24,27,37), severe disease can occur in...

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“…However its increasing use, especially in prophylaxis treatments among transplanted patients and in immune-compromised hosts (cancer, AIDS), has led to the emergence of resistant viral strains. [4,5] It is now generally agreed that cell mediated immunity to several infectious agents is regulated by two distinct T cell cytokine patterns. The production of Th1 cytokines such as interferon-g (IFN-g), interleukins-2 and -12 (IL-2, IL-12), is generally associated with resistance to infection.…”

Section: Introductionmentioning

confidence: 99%

Facile Biocatalytic Access to 9‐Fluorenylmethyl Polyglycosides: Evaluation of Antiviral Activity on Immunocompetent Cells

Tramice¹,

Arena²,

Gregorio³

et al. 2008

ChemMedChem

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The biological activities of a series of mono- and oligosaccharides (beta-xylosides and alpha-glucosides) of 9-fluorenylmethanol were investigated together with mono-beta-galactoside and beta-glucoside of this aglycone, produced by biocatalytic routes. By using marine glycoside hydrolases and inexpensive donors such as maltose or xylan, access to mono-alpha-glucoside or mono-beta-xyloside of 9-fluorenylmethanol was obtained. Additionally, interesting polyglycoside derivatives were isolated. Biological testing indicated that in vitro treatment with these carbohydrate derivatives may influence the balance of cytokines in the environment of human peripheral blood mononuclear cells (PBMC), restricting the harmful effect of herpes simplex type 2 replication. In fact, these carbohydrate derivatives tested in WISH cells did not show any significant antiviral activity.

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Fulminant, Acyclovir-Resistant, Herpes Simplex Virus Type 2 Hepatitis in an Immunocompetent Woman

Cited by 52 publications

References 25 publications

Resistance of Herpes Simplex Viruses to Nucleoside Analogues: Mechanisms, Prevalence, and Management

Resistance of Herpes Simplex Viruses to Nucleoside Analogues: Mechanisms, Prevalence, and Management

Diverse Herpes Simplex Virus Type 1 Thymidine Kinase Mutants in Individual Human Neurons and Ganglia

Facile Biocatalytic Access to 9‐Fluorenylmethyl Polyglycosides: Evaluation of Antiviral Activity on Immunocompetent Cells

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