In vitro antiviral efficacy of the ganciclovir complexed with β-cyclodextrin on human cytomegalovirus clinical strains

2002 ◽  
Vol 54 (2) ◽  
pp. 121-127 ◽  
Author(s):  
Céline Nicolazzi ◽  
Véronique Venard ◽  
Alain Le Faou ◽  
Chantal Finance
Keyword(s):  
Human Cytomegalovirus ◽  
Clinical Strains ◽  
Antiviral Efficacy

scholarly journals The Artemisinin Derivative Artemisone Is a Potent Inhibitor of Human Cytomegalovirus Replication

2018 ◽  
Vol 62 (7) ◽  
Author(s):  
E. Oiknine-Djian ◽  
Y. Weisblum ◽  
A. Panet ◽  
H. N. Wong ◽  
R. K. Haynes ◽  
...  
Keyword(s):  
Human Cytomegalovirus ◽  
Clinical Studies ◽  
Ex Vivo ◽  
Antiviral Treatment ◽  
Lung Fibroblasts ◽  
Reversible Inhibitor ◽  
Artemisinin Derivative ◽  
Viral Kinetics ◽  
Antiviral Efficacy

ABSTRACTHuman cytomegalovirus (HCMV) is a major cause of disease in immunocompromised individuals and the most common cause of congenital infection and neurosensorial disease. The expanding target populations for HCMV antiviral treatment along with the limitations of the currently available HCMV DNA polymerase inhibitors underscore the need for new antiviral agents with alternative modes of action. The antimalarial artemisinin derivative artesunate was shown to inhibit HCMVin vitroyet has demonstrated limited antiviral efficacyin vivo, prompting our search for more potent anti-HCMV artemisinin derivatives. Here we show that the innovative artemisinin derivative artemisone, which has been screened for its activity against malaria parasites in human clinical studies, is a potent and noncytotoxic inhibitor of HCMV. Artemisone exhibited an antiviral efficacy comparable to that of ganciclovir (50% effective concentration, 1.20 ± 0.46 μM) in human foreskin fibroblasts, with enhanced relative potency in lung fibroblasts and epithelial cells. Significantly, the antiviral efficacy of artemisone was consistently ≥10-fold superior to that of artesunate in all cells. Artemisone effectively inhibited both laboratory-adapted and low-passage-number clinical strains, as well as drug-resistant HCMV strains. By using quantitative viral kinetics and gene expression studies, we show that artemisone is a reversible inhibitor targeting an earlier phase of the viral replication cycle than ganciclovir. Importantly, artemisone most effectively inhibited HCMV infectionex vivoin a clinically relevant multicellular model of integral human placental tissues maintained in organ culture. Our promising findings encourage preclinical and clinical studies of artemisone as a new inhibitor against HCMV.

scholarly journals Cellular and Viral Control over the Initial Events of Human Cytomegalovirus Experimental Latency in CD34+ Cells

2010 ◽  
Vol 84 (11) ◽  
pp. 5594-5604 ◽  
Author(s):  
Ryan T. Saffert ◽  
Rhiannon R. Penkert ◽  
Robert F. Kalejta
Keyword(s):  
Gene Expression ◽  
Human Cytomegalovirus ◽  
Nuclear Body ◽  
Immune Defense ◽  
Lytic Infection ◽  
Viral Gene ◽  
Viral Control ◽  
Clinical Strains ◽  
Early Protein

ABSTRACT Human cytomegalovirus (HCMV) persists for the life of its host by establishing a latent infection. The identification of viral and cellular determinants of latency is the first step toward developing antiviral treatments that target and might clear or control the reservoir of latent virus. HCMV latency is established in CD34+ cells when expression of viral immediate early (IE) proteins that initiate lytic infection is silenced. Viral IE gene expression during lytic infection is controlled by a cellular intrinsic immune defense mediated by promyelocytic leukemia nuclear body (PML-NB) proteins such as Daxx and histone deacetylases (HDACs). This defense is inactivated at the start of lytic infection by the HCMV virion tegument protein pp71, which upon viral entry traffics to the nucleus and induces Daxx degradation. Here we show that a similar defense is present, active, and not neutralized during experimental latency in CD34+ cells infected in vitro because tegument-delivered pp71 remains in the cytoplasm. Artificial inactivation of this defense by HDAC inhibition or Daxx knockdown rescues viral IE gene expression upon infection of CD34+ cells with a laboratory-adapted viral strain but not with clinical strains. Interestingly, coinfection of CD34+ cells with clinical viral strains blocked the ability of an HDAC inhibitor to activate IE1 and early protein expression during infection with a laboratory-adapted strain. This suggests that in addition to the intrinsic defense, HCMV clinical strains contribute an HDAC-independent, trans-acting dominant means of control over viral gene expression during the early stages of experimental HCMV latency modeled in vitro in CD34+ cells.

scholarly journals Coding potential of laboratory and clinical strains of human cytomegalovirus

2003 ◽  
Vol 100 (25) ◽  
pp. 14976-14981 ◽  
Author(s):  
E. Murphy ◽  
D. Yu ◽  
J. Grimwood ◽  
J. Schmutz ◽  
M. Dickson ◽  
...  
Keyword(s):  
Human Cytomegalovirus ◽  
Clinical Strains ◽  
Coding Potential

scholarly journals Interaction of the Putative Human Cytomegalovirus Portal Protein pUL104 with the Large Terminase Subunit pUL56 and Its Inhibition by Benzimidazole-d-Ribonucleosides

2005 ◽  
Vol 79 (23) ◽  
pp. 14660-14667 ◽  
Author(s):  
Alexandra Dittmer ◽  
John C. Drach ◽  
Leroy B. Townsend ◽  
Anke Fischer ◽  
Elke Bogner
Keyword(s):  
Dna Replication ◽  
Human Cytomegalovirus ◽  
Unit Length ◽  
Large Subunit ◽  
Intracellular Localization ◽  
Direct Interaction ◽  
Portal Protein ◽  
Specific Association ◽  
Carboxy Terminal

ABSTRACT Herpesvirus DNA replication leads to unit length genomes that are translocated into preformed procapsids through a unique portal vertex. The translocation is performed by the terminase that cleaves the DNA and powers the insertion by its ATPase activity. Recently, we demonstrated that the putative human cytomegalovirus (HCMV) portal protein, pUL104, also forms high-molecular-weight complexes. Analyses now have been performed to determine the intracellular localization and identification of interaction partners of pUL104. In infected cells, HCMV pUL104 was found to be predominantly localized throughout the nucleus as well as in cytoplasmic clusters at late times of infection. The latter localization was abolished by phosphonoacetic acid, an inhibitor of viral DNA replication. Immunofluorescence revealed that pUL104 colocalized with pUL56, the large subunit of the HCMV terminase. Specific association of in vitro translated pUL104 with the carboxy-terminal half of GST-UL56C was detected. By using coimmunoprecipitations a direct interaction with pUL56 was confirmed. In addition, this interaction was no longer detected when the benzimidazole-d-nucleosides BDCRB or Cl4RB were added, thus indicating that these HCMV inhibitors block the insertion of the DNA into the capsid by preventing a necessary interaction of pUL56 with the portal. Electron microscopy revealed that in the presence of Cl4RB DNA is not packaged into capsids and these capsids failed to egress from the nucleus. Furthermore, pulsed-field gel electrophoresis showed that DNA concatemers synthesized in the presence of the compound failed to be processed.

In vitro and in vivo pathogenicity of Salmonella enteritidis clinical strains isolated from North America

2011 ◽  
Vol 193 (11) ◽  
pp. 811-821 ◽  
Author(s):  
Devendra H. Shah ◽  
Xiaohui Zhou ◽  
Tarek Addwebi ◽  
Margaret A. Davis ◽  
Douglas R. Call
Keyword(s):  
North America ◽  
Salmonella Enteritidis ◽  
Clinical Strains

scholarly journals Human Cytomegalovirus Infection Enhances NK Cell Activity In Vitro

2016 ◽  
Vol 2 (7) ◽  
pp. e89 ◽  
Author(s):  
Astrid Tschan-Plessl ◽  
Martin Stern ◽  
Laurent Schmied ◽  
Christelle Retière ◽  
Hans H. Hirsch ◽  
...  
Keyword(s):  
Human Cytomegalovirus ◽  
Cytomegalovirus Infection ◽  
Nk Cell ◽  
Cell Activity ◽  
Nk Cell Activity ◽  
Human Cytomegalovirus Infection

scholarly journals Cellular Pharmacokinetics and Intracellular Activity of the Novel Peptide Deformylase Inhibitor GSK1322322 against Staphylococcus aureus Laboratory and Clinical Strains with Various Resistance Phenotypes: Studies with Human THP-1 Monocytes and J774 Murine Macrophages

2015 ◽  
Vol 59 (9) ◽  
pp. 5747-5760 ◽  
Author(s):  
Frédéric Peyrusson ◽  
Deborah Butler ◽  
Paul M. Tulkens ◽  
Françoise Van Bambeke
Keyword(s):  
Staphylococcus Aureus ◽  
Peptide Deformylase ◽  
Cell Fractionation ◽  
Content Type ◽  
Clinical Strains ◽  
Cellular Pharmacokinetics ◽  
Intracellular Activity ◽  
Static Concentration ◽  
Infected Cells

ABSTRACTGSK1322322 is a peptide deformylase inhibitor active againstStaphylococcus aureusstrains resistant to currently marketed antibiotics. Our aim was to assess the activity of GSK1322322 against intracellularS. aureususing anin vitropharmacodynamic model and, in parallel, to examine its cellular pharmacokinetics and intracellular disposition. For intracellular activity analysis, we used an established model of human THP-1 monocytes and tested one fully susceptibleS. aureusstrain (ATCC 25923) and 8 clinical strains with resistance to oxacillin, vancomycin, daptomycin, macrolides, clindamycin, linezolid, or moxifloxacin. Uptake, accumulation, release, and subcellular distribution (cell fractionation) of [14C]GSK1322322 were examined in uninfected murine J774 macrophages and uninfected and infected THP-1 monocytes. GSK1322322 demonstrated a uniform activity against the intracellular forms of allS. aureusstrains tested, disregarding their resistance phenotypes, with a maximal relative efficacy (Emax) of a 0.5 to 1 log10CFU decrease compared to the original inoculum within 24 h and a static concentration (Cs) close to its MIC in broth. Influx and efflux were very fast (<5 min to equilibrium), and accumulation was about 4-fold, with no or a minimal effect of the broad-spectrum eukaryotic efflux transporter inhibitors gemfibrozil and verapamil. GSK1322322 was recovered in the cell-soluble fraction and was dissociated from the main subcellular organelles and from bacteria (in infected cells). The results of this study show that GSK1322322, as a typical novel deformylase inhibitor, may act against intracellular forms ofS. aureus. They also suggest that GSK1322322 has the ability to freely diffuse into and out of eukaryotic cells as well as within subcellular compartments.

scholarly journals Effect of incorporation of cidofovir into DNA by human cytomegalovirus DNA polymerase on DNA elongation.

1997 ◽  
Vol 41 (3) ◽  
pp. 594-599 ◽  
Author(s):  
X Xiong ◽  
J L Smith ◽  
M S Chen
Keyword(s):  
Dna Synthesis ◽  
Dna Polymerase ◽  
Human Cytomegalovirus ◽  
Chain Elongation ◽  
Exonuclease Activity ◽  
Dna Chain ◽  
Alternate Substrate

Cidofovir (CDV) (HPMPC) has potent in vitro and in vivo activity against human cytomegalovirus (HCMV), CDV diphosphate (CDVpp), the putative antiviral metabolite of CDV, is an inhibitor and an alternate substrate of HCMV DNA polymerase. CDV is incorporated with the correct complementation to dGMP in the template, and the incorporated CDV at the primer end is not excised by the 3'-to-5' exonuclease activity of HCMV DNA polymerase. The incorporation of a CDV molecule causes a decrease in the rate of DNA elongation for the addition of the second natural nucleotide from the singly incorporated CDV molecule. The reduction in the rate of DNA (36-mer) synthesis from an 18-mer by one incorporated CDV is 31% that of the control. However, the fidelity of HCMV DNA polymerase is maintained for the addition of the nucleotides following a single incorporated CDV molecule. The rate of DNA synthesis by HCMV DNA polymerase is drastically decreased after the incorporation of two consecutive CDV molecules; the incorporation of a third consecutive CDV molecule is not detectable. Incorporation of two CDV molecules separated by either one or two deoxynucleoside monophosphates (dAMP, dGMP, or dTMP) also drastically decreases the rate of DNA chain elongation by HCMV DNA polymerase. The rate of DNA synthesis decreases by 90% when a template which contains one internally incorporated CDV molecule is used. The inhibition by CDVpp of DNA synthesis by HCMV DNA polymerase and the inability of HCMV DNA polymerase to excise incorporated CDV from DNA may account for the potent and long-lasting anti-CMV activity of CDV.

scholarly journals Human Cytomegalovirus Replication and Infection-Induced Syncytia Formation in Labial, Foreskin, and Fetal Lung Fibroblasts

Viruses ◽  
2021 ◽  
Vol 13 (12) ◽  
pp. 2355
Author(s):  
Alexis Aguiar ◽  
Melissa Galinato ◽  
Maite’ Bradley Silva ◽  
Bryant Toth ◽  
Michael A. McVoy ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Human Cytomegalovirus ◽  
Fetal Lung ◽  
Lung Fibroblasts ◽  
Anatomical Site ◽  
Cmv Infection ◽  
Viral Spread ◽  
Syncytia Formation

Only a handful of cell types, including fibroblasts, epithelial, and endothelial cells, can support human cytomegalovirus (CMV) replication in vitro, in striking contrast to the situation in vivo. While the susceptibility of epithelial and endothelial cells to CMV infection is strongly modulated by their anatomical site of origin, multiple CMV strains have been successfully isolated and propagated on fibroblasts derived from different organs. As oral mucosal cells are likely involved in CMV acquisition, we sought to evaluate the ability of infant labial fibroblasts to support CMV replication, compared to that of commonly used foreskin and fetal lung fibroblasts. No differences were found in the proportion of cells initiating infection, or in the amounts of viral progeny produced after exposure to the fibroblast-adapted CMV strain AD169 or to the endothelial cell-adapted strain TB40/E. Syncytia formation was, however, significantly enhanced in infected labial and lung fibroblasts compared to foreskin-derived cells, and did not occur after infection with AD169. Together, these data indicate that fibroblast populations derived from different tissues are uniformly permissive to CMV infection but retain phenotypic differences of potential importance for infection-induced cell–cell fusion, and ensuing viral spread and pathogenesis in different organs.

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