Identification and characterization of acyclovir-resistant clinical HSV-1 isolates from children

Wang, Yi; Wang, Qi; Zhu, Qing; Zhou, Rong; Liu, Jinsong; Peng, Tao

doi:10.1016/j.jcv.2011.06.009

Cited by 46 publications

(35 citation statements)

References 29 publications

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“…In such patients, a low prevalence of ACV resistance between 0.3 and 0.7% has been described (4,9,34,35). Conversely, Wang et al (36) reported an unexpectedly high rate of 4.0% ACV-resistant HSV-1 strains in immunocompetent children with oral herpetic lesions, and Duan et al (37) described a prevalence rate of 6.4% ACV-resistant HSV-1 strains in patients with recurrent herpetic keratitis. However, it has to be considered for the interpretation of the present findings that there are some limitations regarding the scarce information about clinical diagnosis, immunocompetence of patients, antiviral therapy modalities, and longitudinal observations.…”

Section: Discussionmentioning

confidence: 99%

Sequence Analysis of Herpes Simplex Virus 1 Thymidine Kinase and DNA Polymerase Genes from over 300 Clinical Isolates from 1973 to 2014 Finds Novel Mutations That May Be Relevant for Development of Antiviral Resistance

Schmidt

Bohn-Wippert

Zell

et al. 2015

Antimicrob Agents Chemother

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A total of 302 clinical herpes simplex virus 1 (HSV-1) strains, collected over 4 decades from 1973 to 2014, were characterized retrospectively for drug resistance. All HSV-1 isolates were analyzed genotypically for nonsynonymous mutations in the thymidine kinase (TK) and DNA polymerase (Pol) genes. The resistance phenotype against acyclovir (ACV) and/or foscarnet (FOS) was examined in the case of novel, unclear, or resistance-related mutations. Twenty-six novel natural polymorphisms could be detected in the TK gene and 69 in the DNA Pol gene. Furthermore, three novel resistance-associated mutations (two in the TK gene and one in the DNA Pol gene) were analyzed, and eight known but hitherto unclear amino acid substitutions (two encoded in TK and six in the DNA Pol gene) could be clarified. Between 1973 and 2014, the distribution of amino acid changes related to the natural gene polymorphisms of TK and DNA Pol remained largely stable. Resistance to ACV was confirmed phenotypically for 16 isolates, and resistance to ACV plus FOS was confirmed for 1 isolate. Acyclovir-resistant strains were observed from the year 1995 onwards, predominantly in immunosuppressed patients, especially those with stem cell transplantation, and the number of ACV-resistant strains increased during the last 2 decades. The data confirm the strong genetic variability among HIV-1 isolates, which is more pronounced in the DNA Pol gene than in the TK gene, and will facilitate considerably the rapid genotypic diagnosis of HSV-1 resistance. Herpes simplex virus 1 (HSV-1) is a ubiquitous human pathogen throughout the world. After primary infection occurring mostly during infancy, the virus remains latently for life in sensory local ganglia. Thereafter, HSV-1 may be reactivated and can cause usually self-limiting orolabial lesions in immunocompetent individuals. In contrast, immunocompromised patients often develop chronic diseases associated with painful and widespread exanthema and/or enanthema. Since its marketing in the 1980s, acyclovir (ACV), a guanosine analog, has been the drug of choice for the treatment of HSV infections; its active form is ACV triphosphate (1, 2). Foscarnet (FOS), a pyrophosphate analog, directly inhibits the viral DNA polymerase (Pol) and can be used successfully as an alternative drug in case of ACV resistance.Acyclovir-resistant HSV-1 isolates have a remarkable clinical prevalence, especially in immunocompromised patients. Summarizing published papers of recent years, the prevalence of ACVresistant HSV strains in immunosuppressed patients ranges between 2.5% and 10.9% (3, 4). For immunocompetent patients, studies between 1985 and 1993 showed that ACV resistance in clinical HSV isolates is Ͻ1.0%, very low (5-8). An overall increase in ACV-resistant HSV strains could not be established in a subsequent study (9).The HSV thymidine kinase (TK) protein is responsible for the conversion of ACV to its active form, and 95% of the mutations encoding antiviral resistance are found in the TK gene (10). Only a few cases of resistanc...

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Section: Discussionmentioning

confidence: 99%

Sequence Analysis of Herpes Simplex Virus 1 Thymidine Kinase and DNA Polymerase Genes from over 300 Clinical Isolates from 1973 to 2014 Finds Novel Mutations That May Be Relevant for Development of Antiviral Resistance

Schmidt

Bohn-Wippert

Zell

et al. 2015

Antimicrob Agents Chemother

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show abstract

“…HSV-1/F (ATCC VR-733) was preserved in our lab. HSV-1/Blue, a TK mutant derived from HSV-1 (KOS) (20), two ACV-resistant clinical HSV-1 strains (HSV-1/106 and HSV-1/153) were a kind gift from Tao Peng (Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences). All viruses were propagated in Vero cells and stored at -809 C until further use.…”

Section: Chemicals and Reagentsmentioning

confidence: 99%

Pentagalloylglucose Blocks the Nuclear Transport and the Process of Nucleocapsid Egress to Inhibit HSV-1 Infection

Jin

Chen

et al. 2016

Jpn J Infect Dis

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SUMMARY: Herpes simplex virus type 1 (HSV-1), a widespread virus, causes a variety of human viral diseases worldwide. The serious threat of drug-resistance highlights the extreme urgency to develop novel antiviral drugs with different mechanisms of action. Pentagalloylglucose (PGG) is a natural polyphenolic compound with significant anti-HSV activity; however, the mechanisms underlying its antiviral activity need to be defined by further studies. In this study, we found that PGG treatment delays the nuclear transport process of HSV-1 particles by inhibiting the upregulation of dynein (a cellular major motor protein) induced by HSV-1 infection. Furthermore, PGG treatment affects the nucleocapsid egress of HSV-1 by inhibiting the expression and disrupting the cellular localization of pEGFP-UL31 and pEGFP-UL34, which are indispensable for HSV-1 nucleocapsid egress from the nucleus. However, the over-expression of pEGFP-UL31 and pEGFP-UL34 could decrease the antiviral effect of PGG. In this study, for the first time, the antiviral activity of PGG against acyclovir-resistant virus was demonstrated in vitro, and the possible mechanisms of its anti-HSV activities were identified based on the inhibition of nuclear transport and nucleocapsid egress in HSV-1. It was further confirmed that PGG could be a promising candidate for HSV therapy, especially for drug-resistant strains.

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“…However, this has resulted in the emergence of drugresistant viruses, including HIV, hepatitis B, and the herpes simplex virus (HSV), which cause drug failures (3,4). Although the drug resistance of HSV to ACV and related drugs, such as famciclovir or valacyclovir, rarely occurs in immunocompetent individuals, it has been more commonly reported in immunocompromised patients, including patients with HIV and transplant recipients (5). A focus on host cellular proteins (6-8) is necessary to overcome drug resistance to antiviral agents, because viruses often change their genomic sequences and acquire drug resistance (4).…”

Section: Introductionmentioning

confidence: 99%

CDK9 inhibitor FIT-039 prevents replication of multiple DNA viruses

Yamamoto¹,

Onogi²,

Kii³

et al. 2014

J. Clin. Invest.

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Identification and characterization of acyclovir-resistant clinical HSV-1 isolates from children

Cited by 46 publications

References 29 publications

Sequence Analysis of Herpes Simplex Virus 1 Thymidine Kinase and DNA Polymerase Genes from over 300 Clinical Isolates from 1973 to 2014 Finds Novel Mutations That May Be Relevant for Development of Antiviral Resistance

Sequence Analysis of Herpes Simplex Virus 1 Thymidine Kinase and DNA Polymerase Genes from over 300 Clinical Isolates from 1973 to 2014 Finds Novel Mutations That May Be Relevant for Development of Antiviral Resistance

Pentagalloylglucose Blocks the Nuclear Transport and the Process of Nucleocapsid Egress to Inhibit HSV-1 Infection

CDK9 inhibitor FIT-039 prevents replication of multiple DNA viruses

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