Acyclovir‐Resistant Corneal HSV‐1 Isolates from Patients with Herpetic Keratitis

Duan, Rui; Vries, Rory D. de; Osterhaus, Albert D. M. E.; Remeijer, Lies; Verjans, Georges M. G. M.

doi:10.1086/590668

Cited by 141 publications

(111 citation statements)

References 14 publications

(38 reference statements)

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“…Combined treatment with acyclovir and steroids is currently used to treat HSK. The extensive use of acyclovir leads to the emergence of resistant virus (3,13,14), so more, alternative therapies are needed. Although Egr-1 participates in many cellular activities, Egr-1 deficiency in mice does not result in obvious defects, except that female mice lacking Egr-1 are infertile (24,25,30).…”

Section: Discussionmentioning

confidence: 99%

“…The anti-HSV drug acyclovir and related nucleoside analogs are used to treat HSK in patients, but acyclovir treatment is hindered by the emergence of drug-resistant viruses, mostly containing mutations in the viral tk gene (3,13,14). We tested the efficacy of suppressing Egr-1 to reduce the replication of an acyclovirresistant HSV-1 mutant, tkLTRZ1, derived from HSV-1 strain KOS without thymidine kinase activity due to an insertion within the tk gene (12).…”

Section: Hsv-1 Infection Enhances Egr-1 Expression In the Corneamentioning

confidence: 99%

“…Currently, a combination of antiherpetic drugs and anti-inflammatory agents is used to treat HSK (17,22,29,32,33). Unfortunately, some patients fail to respond to this regimen or develop virus with resistance to antiherpetic drugs (3,13,14), so additional alternative therapies are needed.…”

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confidence: 99%

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Suppression of Transcription Factor Early Growth Response 1 Reduces Herpes Simplex Virus 1-Induced Corneal Disease in Mice

Yao

Chen

et al. 2012

J Virol

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bHerpes simplex virus 1 replication initiates angiogenesis and inflammation in the cornea. This can result in herpetic stromal keratitis (HSK), which is a leading cause of infection-induced corneal blindness. Host cellular factors mediate the progression of HSK, but little is known about these cellular factors and their mechanisms of action. We show here that the expression of the cellular transcription factor early growth response 1 (Egr-1) in HSV-1-infected mouse corneas was enhanced. Enhanced Egr-1 expression aggravated HSK by increasing viral replication and subsequent neovascularization with high levels of potent angiogenic factors, fibroblast growth factor 2, and vascular endothelial growth factor. Furthermore, Egr-1 deficiency due to a targeted disruption of the gene or knockdown of Egr-1 expression topically using a DNA-based enzyme significantly reduced HSK by decreasing both viral replication and the angiogenic response. The present study provides the first evidence that endogenous Egr-1 aggravates HSK and that blocking Egr-1 reduces corneal damage.

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Section: Discussionmentioning

confidence: 99%

Section: Hsv-1 Infection Enhances Egr-1 Expression In the Corneamentioning

confidence: 99%

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Suppression of Transcription Factor Early Growth Response 1 Reduces Herpes Simplex Virus 1-Induced Corneal Disease in Mice

Yao

Chen

et al. 2012

J Virol

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“…Contra esse vírus, o GCV também apresentou-se eficaz, inibindo completamente a sua replicação em todas as concentrações testadas (Fig.1). A atividade do GCV frente ao HSV-1 foi demonstrada anteriormente (Duan et al 2008). Porém, foram necessárias concentrações maiores desse fármaco para observar-se efeito antiviral frente ao BoHV-5, e frente ao BoHV-1 o GCV foi ineficaz.…”

Section: Discussionunclassified

Atividade de três drogas antivirais sobre os herpesvírus bovino tipos 1, 2 e 5 em cultivo celular

et al. 2010

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The activity of three anti-herpetic drugs (Acyclovir [ACV], Gancyclovir [GCV] and Foscarnet [PFA]) was tested against bovine herpesvirus 1 (BoHV-1), 2 (BoHV-2) and 5 (BoHV-5) in vitro using the plaque reduction assay. Different drug concentrations were tested against one hundred 50% tissue culture infectious dose (TCID 50 ) of the respective viruses. Drug concentrations lower than 200μg/mL resulted in viability rates of more than 80% for MDBK and Hep2 cells in the MTT test (3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide). The selectivity index (IS) of the drugs was calculated dividing the concentration of the drug that is cytotoxic for 50% of the cells (CC 50 ) by the concentration of the drug that was effective in reducing by 50% the number of viral plaques (EC 50 ) for the three herpesviruses. Thus, ACV was shown to be moderately active against BoHV-1 (EC 50 : 112.9μg/mL; IS: 4.5), BoHV-2 (EC 50 : 114.2μg/mL; IS: 4.5) and BoHV-5 (EC 50 : 96.9μg/mL; IS: 5.3). GCV was effective against BoHV-2 (EC 50 : 33.5μg/mL; IS: 16.6), moderately effective against BoHV-5 (EC 50 : 123.2μg/mL; IS: 4.5) and poorly active against BoHV-1 (EC 50 : 335.8μg/mL; IS: 1.7). PFA exhibited the highest antiviral activity, being the only drug that, at concentration of 100μg/mL, completely inhibited plaque formation by all three viruses. PFA was the most effective in vitro against BoHV-1 (EC 50 : 29.5μg/mL; IS: 42.2), BoHV-2 (EC 50 : 45.2μg/mL; IS: 27.6) and BoHV-5 (EC 50 : 7.8μg/mL; IS: 160.6). Thus, the results indicate that PFA is a promising candidate for experimental therapeutic testing in vivo against bovine herpesviruses.INDEX TERMS: Antivirals, BoHV-1, BoHV-2, BoHV-5, Foscarnet, Gancyclovir, Acyclovir. INTRODUÇÃOOs herpesvírus bovino tipos 1 (BoHV-1), 2 (BoHV-2) e 5 (BoHV-5) são vírus DNA de cadeia dupla linear, que possuem um capsídeo de simetria icosaédrica e envelope lipoprotéico, classificados na família Herpesviridae, subfamília Alphaherpesvirinae. Esses vírus estabelecem e reativam infecções latentes em seus hospedeiros, propriedade que permite a sua manutenção na natureza (Rock et al. 1992, Roizman 1992. O BoHV-1 e 5 pertencem ao gênero Varicellovirus, e o BoHV-2 é classificado no gêne-ro Simplexvirus (Roizman 1992). O BoHV-1 é associado com doença respiratória (rinotraqueíte infecciosa bovina, IBR), conjuntivite, vulvovaginite/balanopostite pustular infecciosa (IPV/IBP), infertilidade transitória e abortos (Roizman 1992, Kahrs 2001. O BoHV-2 é associado à mamilite herpética bovina (BHM), doença vesicular e erosiva do úbere e tetos, que acomete principalmente vacas leiteiras de primeira cria (Kahrs 2001). O BoHV-5 é o agente da meningoencefalite herpética, doença geralmente fatal em bovinos jovens, e que ocorre com frequência na Argentina e no Brasil (Carrillo et al. 1983, Rissi et al. 2006.Historicamente, os herpesvírus humanos têm sido alvo para o desenvolvimento e teste de fármacos antivirais. O Aciclovir (ACV) e o Ganciclovir (GCV) são análogos de nucleosídeos, cujas moléculas consistem de uma guanina ass...

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“…However, ACV treatment is hindered by the emergence of drug-resistant viruses, which are estimated to occur in ϳ6% of treated immunocompromised patients (3,6). ACV resistance has also been reported in immunocompetent patients with eye infections (7,8). The majority (Ͼ90%) of ACV-resistant clinical isolates contain mutations in the thymidine kinase (tk) gene, which encodes the protein that activates ACV (3,5).…”

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confidence: 99%

Thymidine Kinase-Negative Herpes Simplex Virus 1 Can Efficiently Establish Persistent Infection in Neural Tissues of Nude Mice

Huang

Yao

Wang

et al. 2017

J Virol

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Herpes simplex virus 1 (HSV-1) establishes latency in neural tissues of immunocompetent mice but persists in both peripheral and neural tissues of lymphocyte-deficient mice. Thymidine kinase (TK) is believed to be essential for HSV-1 to persist in neural tissues of immunocompromised mice, because infectious virus of a mutant with defects in both TK and UL24 is detected only in peripheral tissues, but not in neural tissues, of severe combined immunodeficiency mice (T. Valyi-Nagy, R. M. Gesser, B. Raengsakulrach, S. L. Deshmane, B. P. Randazzo, A. J. Dillner, and N. W. Fraser, Virology 199:484 -490, 1994, https://doi.org/10.1006/viro .1994.1150). Here we find infiltration of CD4 and CD8 T cells in peripheral and neural tissues of mice infected with a TK-negative mutant. We therefore investigated the significance of viral TK and host T cells for HSV-1 to persist in neural tissues using three genetically engineered mutants with defects in only TK or in both TK and UL24 and two strains of nude mice. Surprisingly, all three mutants establish persistent infection in up to 100% of brain stems and 93% of trigeminal ganglia of adult nude mice at 28 days postinfection, as measured by the recovery of infectious virus. Thus, in mouse neural tissues, host T cells block persistent HSV-1 infection, and viral TK is dispensable for the virus to establish persistent infection. Furthermore, we found 30-to 200-fold more virus in neural tissues than in the eye and detected glycoprotein C, a true late viral antigen, in brainstem neurons of nude mice persistently infected with the TK-negative mutant, suggesting that adult mouse neurons can support the replication of TK-negative HSV-1.IMPORTANCE Acyclovir is used to treat herpes simplex virus 1 (HSV-1)-infected immunocompromised patients, but treatment is hindered by the emergence of drugresistant viruses, mostly those with mutations in viral thymidine kinase (TK), which activates acyclovir. TK mutants are detected in brains of immunocompromised patients with persistent infection. However, answers to the questions as to whether TKnegative (TK Ϫ ) HSV-1 can establish persistent infection in brains of immunocompromised hosts and whether neurons in vivo are permissive for TK Ϫ HSV-1 remain elusive. Using three genetically engineered HSV-1 TK Ϫ mutants and two strains of nude mice deficient in T cells, we found that all three HSV-1 TK Ϫ mutants can efficiently establish persistent infection in the brain stem and trigeminal ganglion and detected glycoprotein C, a true late viral antigen, in brainstem neurons. Our study provides evidence that TK Ϫ HSV-1 can persist in neural tissues and replicate in brain neurons of immunocompromised hosts.

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Acyclovir‐Resistant Corneal HSV‐1 Isolates from Patients with Herpetic Keratitis

Cited by 141 publications

References 14 publications

Suppression of Transcription Factor Early Growth Response 1 Reduces Herpes Simplex Virus 1-Induced Corneal Disease in Mice

Suppression of Transcription Factor Early Growth Response 1 Reduces Herpes Simplex Virus 1-Induced Corneal Disease in Mice

Atividade de três drogas antivirais sobre os herpesvírus bovino tipos 1, 2 e 5 em cultivo celular

Thymidine Kinase-Negative Herpes Simplex Virus 1 Can Efficiently Establish Persistent Infection in Neural Tissues of Nude Mice

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