scholarly journals In Vitro Activities of Benzimidazole d- and l-Ribonucleosides against Herpesviruses

2003 ◽  
Vol 47 (7) ◽  
pp. 2186-2192 ◽  
Author(s):  
Stephanie L. Williams ◽  
Caroll B. Hartline ◽  
Nicole L. Kushner ◽  
Emma A. Harden ◽  
Deborah J. Bidanset ◽  
...  
Keyword(s):  
Clinical Manifestations ◽  
Human Herpesvirus ◽  
Significant Activity ◽  
Varicella Zoster ◽  
Barr Virus ◽  
Culture Cells ◽  
Simplex Virus ◽  
Human Cmv ◽  
Hsv 1

ABSTRACT Herpes simplex virus types 1 and 2 (HSV-1 and HSV-2), varicella-zoster virus (VZV), cytomegalovirus (CMV), Epstein-Barr virus (EBV), human herpesvirus 6 (HHV-6), and human herpesvirus 8 (HHV-8) are responsible for a number of clinical manifestations in both normal and immunocompromised individuals. The parent benzimidazole ribonucleosides evaluated in this series, 2-bromo-5,6-dichloro-1-(β-d-ribofuranosyl)benzimidazole (BDCRB) and maribavir (1263W94), are potent and selective inhibitors of human CMV replication. These nucleosides act by two different mechanisms. BDCRB blocks the processing and maturation of viral DNA, whereas 1263W94 inhibits the viral enzyme pUL97 and interferes with DNA synthesis. In the present study, we have evaluated the in vitro antiviral activity of BDCRB, an analog, GW275175X (175X), and 1263W94 against the replication of HSV-1, HSV-2, VZV, CMV, EBV, HHV-6, and HHV-8. By using various methodologies, significant activity was observed against human CMV and EBV but not against HSV-1, HSV-2, VZV, HHV-6, or HHV-8. Plaque reduction assays performed on a variety of laboratory and clinical isolates of human CMV indicated that all strains, including those resistant to ganciclovir (GCV) and foscarnet, were sensitive to all three benzimidazole ribonucleosides, with mean 50% effective concentration values of about 1 to 5 μM compared to that of GCV at 6 μM. The toxicity of these compounds in tissue culture cells appeared to be similar to that observed with GCV. These results demonstrate that the benzimidazole ribonucleosides are active against human CMV and EBV and suggest that they may be useful for the treatment of infections caused by these herpesviruses.

scholarly journals Inhibition of Herpesvirus Replication by 5-Substituted 4′-Thiopyrimidine Nucleosides

2009 ◽  
Vol 53 (12) ◽  
pp. 5251-5258 ◽  
Author(s):  
Mark N. Prichard ◽  
Debra C. Quenelle ◽  
Caroll B. Hartline ◽  
Emma A. Harden ◽  
Geraldine Jefferson ◽  
...  
Keyword(s):  
Human Herpesvirus ◽  
Good Activity ◽  
Varicella Zoster ◽  
Barr Virus ◽  
Resistant Strains ◽  
Epstein Barr ◽  
Simplex Virus ◽  
Hsv 1

ABSTRACT A series of 4′-thionucleosides were synthesized and evaluated for activities against orthopoxviruses and herpesviruses. We reported previously that one analog, 5-iodo-4′-thio-2′-deoxyuridine (4′-thioIDU), exhibits good activity both in vitro and in vivo against two orthopoxviruses. This compound also has good activity in cell culture against many of the herpesviruses. It inhibited the replication of herpes simplex virus type 1 (HSV-1), HSV-2, and varicella-zoster virus with 50% effective concentrations (EC50s) of 0.1, 0.5, and 2 μM, respectively. It also inhibited the replication of human cytomegalovirus (HCMV) with an EC50 of 5.9 μM but did not selectively inhibit Epstein-Barr virus, human herpesvirus 6, or human herpesvirus 8. While acyclovir-resistant strains of HSV-1 and HSV-2 were comparatively resistant to 4′-thioIDU, it retained modest activity (EC50s of 4 to 12 μM) against these strains. Some ganciclovir-resistant strains of HCMV also exhibited reduced susceptibilities to the compound, which appeared to be related to the specific mutations in the DNA polymerase, consistent with the observed incorporation of the compound into viral DNA. The activity of 4′-thioIDU was also evaluated using mice infected intranasally with the MS strain of HSV-2. Although there was no decrease in final mortality rates, the mean length of survival after inoculation increased significantly (P < 0.05) for all animals receiving 4′-thioIDU. The findings from the studies presented here suggest that 4′-thioIDU is a good inhibitor of some herpesviruses, as well as orthopoxviruses, and this class of compounds warrants further study as a therapy for infections with these viruses.

scholarly journals In Vitro Activity and Mechanism of Action of Methylenecyclopropane Analogs of Nucleosides against Herpesvirus Replication

2005 ◽  
Vol 49 (3) ◽  
pp. 1039-1045 ◽  
Author(s):  
Earl R. Kern ◽  
Nicole L. Kushner ◽  
Caroll B. Hartline ◽  
Stephanie L. Williams-Aziz ◽  
Emma A. Harden ◽  
...  
Keyword(s):  
Mechanism Of Action ◽  
Human Herpesvirus ◽  
Murine Cytomegalovirus ◽  
Enzyme Linked Immunosorbent Assay ◽  
Herpesvirus Type ◽  
Varicella Zoster ◽  
Barr Virus ◽  
Simplex Virus ◽  
Hsv 1

ABSTRACT We have reported previously that methylenecyclopropane analogs of nucleosides have excellent activity against certain members of the herpesvirus family. A second generation, the 2,2-bis-hydroxymethyl derivatives, were synthesized, and 18 compounds were tested for activity in vitro against herpes simplex virus types 1 and 2 (HSV-1 and HSV-2), human and murine cytomegalovirus (HCMV and MCMV), varicella-zoster virus (VZV), and Epstein-Barr virus (EBV). Selected analogs were also evaluated against human herpesvirus type 6 (HHV-6) and HHV-8. None of the 18 compounds had activity against HSV-1 or HSV-2, but four were active against VZV by plaque reduction (PR) assay at 50% effective concentration (EC50) levels of ≤50 μM. Six of the 18 compounds were active against HCMV by cytopathic effect or PR assays with EC50s of 0.5 to 44 μM, and all were active against MCMV by PR (0.3 to 54 μM). Four of the compounds were active against EBV by enzyme-linked immunosorbent assay (<0.3 to 4.4 μM). Four compounds with CMV activity were also active against HHV-6A and HHV-6B (0.7 to 28 μM), and three compounds were active against HHV-8 (5.5 to 16 μM). One of these, ZSM-I-62, had particularly good activity against CMV, HHV-6, and HHV-8, with EC50s of 0.7 to 8 μM. Toxicity was evaluated in adherent and nonadherent cells, and minimal cytotoxicity was observed. Mechanism of action studies with HCMV suggested that these compounds are phosphorylated by the ppUL97 phosphotransferase and are potent inhibitors of viral DNA synthesis. These results indicate that at least one of these compounds may have potential for use in treating CMV and other herpesvirus infections in humans.

scholarly journals Amphipathic DNA Polymers Exhibit Antiherpetic Activity In Vitro and In Vivo

2008 ◽  
Vol 52 (8) ◽  
pp. 2727-2733 ◽  
Author(s):  
David I. Bernstein ◽  
Nathalie Goyette ◽  
Rhonda Cardin ◽  
Earl R. Kern ◽  
Guy Boivin ◽  
...  
Keyword(s):  
Antiviral Activity ◽  
Broad Spectrum ◽  
Parent Compound ◽  
Human Herpesvirus ◽  
Varicella Zoster ◽  
Barr Virus ◽  
Simplex Virus ◽  
Acid Stable

ABSTRACT Phosphorothioated oligonucleotides have a sequence-independent antiviral activity as amphipathic polymers (APs). The activity of these agents against herpesvirus infections in vitro and in vivo was investigated. The previously established sequence-independent, phosphorothioation-dependent antiviral activity of APs was confirmed in vitro by showing that a variety of equivalently sized homo- and heteropolymeric AP sequences were similarly active against herpes simplex virus type 1 (HSV-1) infection in vitro compared to the 40mer degenerate parent compound (REP 9), while the absence of phosphorothioation resulted in the loss of antiviral activity. In addition, REP 9 demonstrated in vitro activity against a broad spectrum of other herpesviruses: HSV-2 (50% effective concentration [EC50], 0.02 to 0.06 μM), human cytomegalovirus (EC50, 0.02 to 0.13 μM), varicella zoster virus (EC50, <0.02 μM), Epstein-Barr virus (EC50, 14.7 μM) and human herpesvirus types 6A/B (EC50, 2.9 to 10.2 μM). The murine microbicide model of genital HSV-2 was then used to evaluate in vivo activity. REP 9 (275 mg/ml) protected 75% of animals from disease and infection when provided 5 or 30 min prior to vaginal challenge. When an acid-stable analog (REP 9C) was used, 75% of mice were protected when treated with 240 mg/ml 5 min prior to infection (P < 0.001), while a lower dose (100 mg/ml) protected 100% of the mice (P < 0.001). The acid stable REP 9C formulation also provided protection at 30 min (83%, P < 0.001) and 60 min (50%, P = 0.07) against disease. These observations suggest that APs may have microbicidal activity and potential as broad-spectrum antiherpetic agents and represent a novel class of agents that should be studied further.

scholarly journals Antiherpesvirus Activities of Two Novel 4′-Thiothymidine Derivatives, KAY-2-41 and KAH-39-149, Are Dependent on Viral and Cellular Thymidine Kinases

2014 ◽  
Vol 58 (8) ◽  
pp. 4328-4340 ◽  
Author(s):  
Natacha Coen ◽  
Sophie Duraffour ◽  
Kazuhiro Haraguchi ◽  
Jan Balzarini ◽  
Joost J. van den Oord ◽  
...  
Keyword(s):  
Herpes Simplex Virus ◽  
Herpes Simplex ◽  
Antiviral Activity ◽  
Epstein Barr Virus ◽  
Varicella Zoster ◽  
Barr Virus ◽  
Epstein Barr ◽  
Simplex Virus ◽  
Hsv 1

ABSTRACTThe emergence of drug-resistant herpesviruses represents a significant problem in clinical practice, primarily in immunocompromised patients. Furthermore, effective antiviral therapies against gammaherpesvirus-associated diseases are lacking. Here, we present two thiothymidine derivatives, KAY-2-41 and KAH-39-149, with different spectra of antiviral activity from those of the reference antiherpetic drugs, showing inhibitory activities against herpes simplex virus, varicella-zoster virus (VZV), and particularly against Epstein-Barr virus, with high selectivityin vitro. While KAY-2-41- and KAH-39-149-resistant herpesviruses were found to harbor mutations in the viral thymidine kinase (TK), these mutations conferred only low levels of resistance to these drugs but high levels to other TK-dependent drugs. Also, antiviral assays in HeLa TK-deficient cells showed a lack of KAY-2-41 and KAH-39-149 activities against herpes simplex virus 1 (HSV-1) and HSV-2 TK-deficient mutants. Furthermore, enzymatic TK assays showed the ability of HSV-1 TK, VZV TK, and cellular TK1 and TK2 to recognize and phosphorylate KAY-2-41 and KAH-39-149. These results demonstrate that the compounds depend on both viral and host TKs to exert antiviral activity. Additionally, the antiviral efficacy of KAH-39-149 proved to be superior to that of KAY-2-41 in a mouse model of gammaherpesvirus infection, highlighting the potential of this class of antiviral agents for further development as selective therapeutics against Epstein-Barr virus.

scholarly journals Comparative Activities of Lipid Esters of Cidofovir and Cyclic Cidofovir against Replication of Herpesviruses In Vitro

2005 ◽  
Vol 49 (9) ◽  
pp. 3724-3733 ◽  
Author(s):  
Stephanie L. Williams-Aziz ◽  
Caroll B. Hartline ◽  
Emma A. Harden ◽  
Shannon L. Daily ◽  
Mark N. Prichard ◽  
...  
Keyword(s):  
Human Cytomegalovirus ◽  
Human Herpesvirus ◽  
Murine Cytomegalovirus ◽  
In Vitro Assays ◽  
Varicella Zoster ◽  
Barr Virus ◽  
Lipid Ester ◽  
Epstein Barr ◽  
Simplex Virus

ABSTRACT Cidofovir (CDV) is an effective therapy for certain human cytomegalovirus (HCMV) infections in immunocompromised patients that are resistant to other antiviral drugs, but the compound is not active orally. To improve oral bioavailability, a series of lipid analogs of CDV and cyclic CDV (cCDV), including hexadecyloxypropyl-CDV and -cCDV and octadecyloxyethyl-CDV and -cCDV, were synthesized and found to have multiple-log-unit enhanced activity against HCMV in vitro. On the basis of the activity observed with these analogs, additional lipid esters were synthesized and evaluated for their activity against herpes simplex virus (HSV) types 1 and 2, human cytomegalovirus, murine cytomegalovirus, varicella-zoster virus (VZV), Epstein-Barr virus (EBV), human herpesvirus 6 (HHV-6), and HHV-8. Using several different in vitro assays, concentrations of drug as low as 0.001 μM reduced herpesvirus replication by 50% (EC50) with the CDV analogs, whereas the cCDV compounds were generally less active. In most of the assays performed, the EC50 values of the lipid esters were at least 100-fold lower than the EC50 values for unmodified CDV or cCDV. The lipid analogs were also active against isolates that were resistant to CDV, ganciclovir, or foscarnet. These results indicate that the lipid ester analogs are considerably more active than CDV itself against HSV, VZV, CMV, EBV, HHV-6, and HHV-8 in vitro, suggesting that they may have potential for the treatment of infections caused by a variety of herpesviruses.

scholarly journals Amplification of the Six Major Human Herpesviruses from Cerebrospinal Fluid by a Single PCR

1999 ◽  
Vol 37 (4) ◽  
pp. 950-953 ◽  
Author(s):  
Sophie Minjolle ◽  
C. Michelet ◽  
I. Jusselin ◽  
M. Joannes ◽  
F. Cartier ◽  
...  
Keyword(s):  
Cerebrospinal Fluid ◽  
Clinical Signs ◽  
Human Herpesvirus ◽  
Varicella Zoster ◽  
Consensus Sequences ◽  
Barr Virus ◽  
Two Samples ◽  
Epstein Barr ◽  
Simplex Virus ◽  
Hsv 1

We used a novel type of primer system, a system that uses stair primers, in which the primer sequences are based on consensus sequences in the DNA polymerase gene of herpesvirus to detect herpesviruses by PCR. A single PCR in a single tube detected the six major herpesviruses that infect the central nervous system: herpes simplex virus type 1 (HSV-1), and type 2 (HSV-2), cytomegalovirus (CMV), Epstein-Barr virus (EBV), varicella-zoster virus (VZV), and human herpesvirus 6 (HHV-6). We used the technique to analyze 142 cerebrospinal fluid (CSF) samples that had been stored at −80°C and compared the results with those obtained previously for the same samples by standard, targeted PCR. Four hundred one targeted PCR tests had been run with the 142 samples to detect HSV-1, HSV-2, CMV, and VZV; screening for EBV and HHV-6 was not prescribed when the samples were initially taken. Eighteen CSF samples tested positive by classic targeted PCR. The herpesvirus consensus PCR detected herpesviruses in 37 samples, including 3 samples with coinfections and 17 viral isolates which were not targeted. Two samples identified as infected by the targeted PCR tested negative by the consensus PCR, and eight samples that tested positive by the consensus PCR were negative by the targeted PCR. One hundred three samples scored negative by both the targeted and the consensus PCRs. This preliminary study demonstrates the value of testing for six different herpesviruses simultaneously by a sensitive and straightforward technique rather than screening only for those viruses that are causing infections as suggested by clinical signs.

scholarly journals Encephalitis in Thailand: A Neglected Disease Increasingly Caused by Enterovirus

2021 ◽  
Vol 6 (3) ◽  
pp. 117
Author(s):  
Pasin Hemachudha ◽  
Sininat Petcharat ◽  
Soawapak Hinjoy ◽  
Abhinbhen W. Saraya ◽  
Thiravat Hemachudha
Keyword(s):  
Human Herpesvirus ◽  
Health Science ◽  
Science Center ◽  
Varicella Zoster ◽  
Barr Virus ◽  
Specific Pcr ◽  
Epstein Barr ◽  
Simplex Virus ◽  
Made In ◽  
Hsv 1

From 2013 to 2018, the Thai Red Cross Emerging Infectious Disease–Health Science Center (TRC-EID-HS), in collaboration with the Department of Disease Control (DDC) and the Ministry of Public Health (MOPH) Thailand, conducted encephalitis surveillance. A total of 1700 cerebrospinal fluid (CSF) samples from patients with encephalitis were tested by a predesigned multiplex PCR. Diagnosis was made in 318 cases (18.7%), 86 (27%) of which were caused by Epstein–Barr virus (EBV), 55 (17.3%) by enteroviruses (EV), 36 (11.3%) by varicella–zoster virus (VZV), 31 (9.7%) by cytomegalovirus (CMV), 25 (7.8%) by herpes simplex virus type 1 (HSV-1), and 20 (6.3%) by human herpesvirus 6 (HHV-6). Results were compared with 3099 CSF samples from patients with encephalitis collected between 2002 to 2012, which were tested by specific PCR assays. Diagnosis was made in 337 (10.9%) of these cases, and 91 (27%) were CMV, 79 (23.4%) were VZV, 72 (21.4%) were EBV, 39 (11.6%) were EVs, 39 (11.6%) were HSV-1, 33 (9.8%) were HSV-2, and 2 (0.6%) were Dengue virus (DENV). The change in the pattern toward EVs as a major cause of viral encephalitis was unexpected, and a change in viral neurotropism may be responsible.

scholarly journals Evaluation of RealStar® Alpha Herpesvirus PCR Kit for Detection of HSV-1, HSV-2, and VZV in Clinical Specimens

2019 ◽  
Vol 2019 ◽  
pp. 1-6 ◽  
Author(s):  
Cyril C. Y. Yip ◽  
Siddharth Sridhar ◽  
Kit-Hang Leung ◽  
Andrew K. W. Cheng ◽  
Kwok-Hung Chan ◽  
...  
Keyword(s):  
Real Time ◽  
Real Time Pcr ◽  
Test Performance ◽  
Analytical Sensitivity ◽  
Pcr Assay ◽  
Clinical Specimens ◽  
Varicella Zoster ◽  
Simplex Virus ◽  
Hsv 1

Several commercial PCR kits are available for detection of herpes simplex virus (HSV) and varicella zoster virus (VZV), but the test performance of one CE-marked in vitro diagnostic kit—RealStar® alpha Herpesvirus PCR Kit—has not been well studied. This study evaluated the performance of RealStar® alpha Herpesvirus PCR Kit 1.0 on the LightCycler® 480 Instrument II for detection and differentiation of HSV-1, HSV-2, and VZV in human clinical specimens. We evaluated the analytical sensitivity of the RealStar® and in-house multiplex real-time PCR assays using serial dilutions of nucleic acids extracted from clinical specimens. The analytical sensitivity of the RealStar® assay was 10, 32, and 100 copies/reaction for HSV-1, HSV-2, and VZV, respectively, which was slightly higher than that of the in-house multiplex real-time PCR assay. Reproducibility of the cycle threshold (Cp) values for each viral target was satisfactory with the intra- and interassay coefficient of variation values below 5% for both assays. One-hundred and fifty-three clinical specimens and 15 proficiency testing samples were used to evaluate the diagnostic performance of RealStar® alpha Herpesvirus PCR Kit against the in-house multiplex real-time PCR assay. The RealStar® assay showed 100% sensitivity and specificity when compared to the in-house assay. Cp values of the RealStar® and in-house assays showed excellent correlation. RealStar® alpha Herpesvirus PCR is a sensitive, specific, and reliable assay for the detection of HSV-1, HSV-2, and VZV, with less extensive verification requirements compared to a laboratory developed assay.

scholarly journals Recent Developments in Viral Load Measurements in Human Herpesviruses

1999 ◽  
Vol 10 (suppl c) ◽  
pp. 33C-40C
Author(s):  
Guy Boivin
Keyword(s):  
Clinical Utility ◽  
Biological Fluids ◽  
Quantitative Polymerase Chain Reaction ◽  
Human Herpesvirus ◽  
Relevant Information ◽  
Varicella Zoster ◽  
Barr Virus ◽  
Recent Developments ◽  
Simplex Virus ◽  
Human Herpesviruses

Recent developments in molecular biology have allowed precise quantitative analysis of herpesvirus DNA in many biological fluids. Th is paper reviews the clinical utility of performing quantitative polymerase chain reaction testing for herpesviruses. In particular, the assessment of the cytomegalovirus (CMV) DNA load in blood with regard to the development of CMV disease in immunocompromised patients is discussed in greater detail. Relevant information exists to support measuring the CMV burden in the blood of AIDS and transplant patients for diagnostic and treatment monitoring purposes, and, to a lesser extent, to envision the monitoring of the circulating Epstein-Barr virus load for the prevention of pose-transplant lymphoproliferative disorders. On the ocher hand, there are controversial data on the clinical utility of measuring the herpes simplex virus (HSV) load in cerebrospinal fluid of patients with HSV encephalitis and on the relationship between the human herpesvirus 8 DNA load in diverse biological fluids and the presence of Kaposi's sarcoma. There is a paucity of information about the clinical impact of quantifying the other human herpesviruses (varicella-zoster virus, and human herpesviruses 6 and 7).

scholarly journals Influence of thyroid hormone disruption on the incidence of shingles

2015 ◽  
Vol 143 (16) ◽  
pp. 3557-3571 ◽  
Author(s):  
A. AJAVON ◽  
D. KILLIAN ◽  
R. ODOM ◽  
R. W. FIGLIOZZI ◽  
F. CHEN ◽  
...  
Keyword(s):  
Thyroid Hormone ◽  
Age Groups ◽  
Human Herpesvirus ◽  
Incidence Rates ◽  
Retrospective Case ◽  
Varicella Zoster ◽  
Its Gene ◽  
History Of ◽  
Simplex Virus ◽  
Hsv 1

SUMMARYThe reactivation of dormant alpha-human herpesvirus (αHHV) has been attributed to various causes often referred to as stressors. However, no clinical study investigating the relationship between stressors and reactivation exists in humans at this time. Herpes simplex virus type-1 (HSV-1), an important αHHV, was shown to have its gene expression and replication regulated by thyroid hormone (TH) using molecular biology approaches. Varicella zoster virus (VZV) is categorized in αHHV superfamily and shares similar homology with HSV-1. We hypothesize that a history of TH imbalance may be associated with the incidence of shingles (VZV reactivation). This current pilot study, based on a hospital medical claims database, was conducted as a retrospective case-controlled investigation to determine if a putative link between TH imbalance and incidence of shingles is present. An odds ratio of 2·95 with a χ2 value of 51·74 was calculated for the total population diagnosed with TH disruption and shingles. Further analyses indicated that African American males exhibited a much higher chance of simultaneous diagnoses. These results show that a TH imbalance history may affect VZV reactivation at different incidence rates in different races and age groups.

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