Acyclovir resistance in herpes simplex encephalitis

Schulte, Eva C.; Sauerbrei, Andreas; Hoffmann, Dieter; Zimmer, Claus; Hemmer, Bernhard; Mühlau, Mark

doi:10.1002/ana.21979

Cited by 64 publications

(31 citation statements)

References 20 publications

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“…The precise role of some mutations remains unclear. The R41H change has been reported previously in TK from both ACV-sensitive and ACV-resistant HSV-1 strains (5,10,15,47,49,51). Here, this change was evidenced in only one sensitive isolate.…”

Section: Discussionsupporting

confidence: 68%

Genotypic Characterization of UL23 Thymidine Kinase and UL30 DNA Polymerase of Clinical Isolates of Herpes Simplex Virus: Natural Polymorphism and Mutations Associated with Resistance to Antivirals

Burrel

Deback

Agut

et al. 2010

Antimicrob Agents Chemother

124

114

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The molecular mechanisms of herpes simplex virus (HSV) resistance to antiviral drugs interfering with viral DNA synthesis reported so far rely on the presence of mutations within UL23 (thymidine kinase [TK]) and UL30 (DNA polymerase) genes. The interpretation of genotypic antiviral resistance assay results requires the clear distinction between resistance mutations and natural interstrain sequence variations. The objectives of this work were to describe extensively the natural polymorphism of UL23 TK and UL30 DNA polymerase among HSV-1 and HSV-2 strains and the amino acid changes potentially associated with HSV resistance to antivirals. The sequence analysis of the full-length UL23 and UL30 genes was performed. Ninety-four drugsensitive clinical isolates (43 HSV-1 and 51 HSV-2) and 3 laboratory strains (KOS, gHSV-2, and MS2) were studied for natural polymorphism, and 25 clinical isolates exhibiting phenotypic traits of resistance to antivirals were analyzed for drug resistance mutations. Our results showed that TK and DNA polymerase are highly conserved among HSV strains, with a weaker variability for HSV-2 strains. This study provided a precise map of the natural polymorphism of both viral enzymes among HSV-1 and HSV-2 isolates, with the identification of 15 and 51 polymorphisms never previously described for TK and DNA polymerase, respectively, which will facilitate the interpretation of genotypic antiviral-resistant testing. Moreover, the genotypic characterization of 25 drug-resistant HSV isolates revealed 8 new amino acid changes located in TK and potentially accounting for acyclovir (ACV) resistance.Herpes simplex virus type 1 (HSV-1) and HSV-2 are responsible for a variety of clinical manifestations (10). In immunocompetent individuals, the symptoms are usually self-limited, whereas severe diseases, sometimes life-threatening, may occur in immunocompromised patients (14,17,26). The discovery of acyclovir (ACV), almost 30 years ago, represents a milestone in the management of HSV infections. The antiviral activity and selectivity of ACV is based on the phosphorylation to its monophosphate form by the virus-encoded thymidine kinase (TK). Then ACV monophosphate is further phosphorylated by cellular thymidilate kinases to the triphosphate form and is incorporated into the growing DNA chain by the viral DNA polymerase, thereby inhibiting replication through chain termination. The decreased activity of TK confers HSV resistance to ACV, resulting in the inability of the drug to inhibit viral replication. Alternative drugs, like foscarnet (FOS), are effective without the requirement of phosphorylation by viral TK. FOS inhibits directly the viral DNA polymerase as a substrate analogue of the pyrophosphate formed during DNA synthesis (23).HSV TK is a 376-amino-acid protein, encoded by the UL23 gene, containing an ATP binding site (codons 51 to 63), a nucleoside binding site (codons 168 to 176 for HSV-1 and 169 to 177 for HSV-2), and a highly conserved cysteine residue at position 336 for HSV-1 and 337 for HSV-2 (2,...

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Section: Discussionsupporting

confidence: 68%

Genotypic Characterization of UL23 Thymidine Kinase and UL30 DNA Polymerase of Clinical Isolates of Herpes Simplex Virus: Natural Polymorphism and Mutations Associated with Resistance to Antivirals

Burrel

Deback

Agut

et al. 2010

Antimicrob Agents Chemother

124

114

View full text Add to dashboard Cite

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“…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%

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

Piret

Boivin

2011

Antimicrob Agents Chemother

465

406

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“…There is one report of a possibly ACV-resistant HSV-1 encephalitis adult patient (15). In that report, virus isolation from the CSF failed, but an amino acid substitution of R41H found in the vTK polypeptide was suspected to be responsible for the ACV resistance, although it has not been virologically confirmed whether the mutation confers ACV resistance.…”

mentioning

confidence: 99%

Neonatal Herpes Encephalitis Caused by a Virologically Confirmed Acyclovir-Resistant Herpes Simplex Virus 1 Strain

et al. 2013

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A neonate with herpes simplex virus 1 encephalitis was treated with intravenous acyclovir. During the course of therapy, the infection became intractable to the treatment and a mutation in the viral thymidine kinase gene (nucleotide G375T, amino acid Q125H) developed. This mutation was demonstrated in vitro to confer acyclovir resistance. CASE REPORTA 13-day-old boy was admitted to National Defense Medical College Hospital due to lethargy and failure to thrive. He was born at 39 weeks 5 days of gestation and 2,558 g birth weight to a healthy 35-year-old mother (gravida 2, para 2). Group B streptococcus (GBS) was detected from the mother's vagina in the third trimester, but the baby's bacterial culture tests performed at birth, including throat, skin, and blood analyses, were negative for GBS. The mother did not have a history of genital herpes. Her herpes simplex virus 1 (HSV-1) and HSV-2 serostatus was not examined, and her history of acyclovir (ACV) use was not clear. Furthermore, the genital swab culture examination for HSV was not performed. On admission, physical examination of the boy revealed skin blisters on the forehead and upper lip. A swab from the blister showed positive and negative reactions for the specific antigens of HSV-1 and HSV-2, respectively, in a direct immunofluorescent antibody assay (Denka Seiken Co. Ltd., Tokyo, Japan) performed by a qualified clinical laboratory (SRL Inc., Tokyo, Japan). A serum sample collected on admission showed positive and negative reactions in the enzyme-linked immunosorbent assay for detection of anti-HSV IgM and IgG antibody (SRL Inc.), respectively. A lumbar puncture revealed pleocytosis (547 cells/l) and an elevated protein level (168 mg/dl) in the cerebrospinal fluid (CSF). The CSF was also positive for HSV-1 DNA, which was determined by a previously reported method (1) in PCR testing (SRL Inc.). The boy was diagnosed as having neonatal herpes encephalitis (NHE), and intravenous highdose ACV (60 mg/kg/day) treatment was initiated. His general status improved with resolution of the skin lesions within a few days of the beginning of treatment. However, the viral load in the CSF determined by TaqMan-based quantitative real-time PCR (SRL Inc.), which dropped temporarily, increased again after 4 weeks from the initiation of ACV treatment (Fig. 1A) without obvious deterioration in clinical symptoms. Because the standard dose of ACV was given and drugs which have antagonistic effects for ACV were not used, we assumed that an ACV-resistant HSV-1 strain had developed. The ACV concentration in the CSF was not measured. Foscarnet, an antiviral drug recommended for treatment of ACV-resistant HSV infections (2), was not immediately available. Therefore, vidarabine (15 mg/kg/day) was added to the therapeutic regimen from the fifth week of the treatment course. Subsequently, HSV-DNA in the CSF decreased to a level that was finally undetectable; hence, the antiviral drug treatment was terminated. Because virus isolation from the CSF of the patient was unsuccessful, as is c...

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Acyclovir resistance in herpes simplex encephalitis

Cited by 64 publications

References 20 publications

Genotypic Characterization of UL23 Thymidine Kinase and UL30 DNA Polymerase of Clinical Isolates of Herpes Simplex Virus: Natural Polymorphism and Mutations Associated with Resistance to Antivirals

Genotypic Characterization of UL23 Thymidine Kinase and UL30 DNA Polymerase of Clinical Isolates of Herpes Simplex Virus: Natural Polymorphism and Mutations Associated with Resistance to Antivirals

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

Neonatal Herpes Encephalitis Caused by a Virologically Confirmed Acyclovir-Resistant Herpes Simplex Virus 1 Strain

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