Antiviral Effects of Artesunate on JC Polyomavirus Replication in COS-7 Cells

Sharma, Biswa Nath; Marschall, Manfred; Rinaldo, Christine Hanssen

doi:10.1128/aac.03714-14

Cited by 34 publications

(27 citation statements)

References 66 publications

(84 reference statements)

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“…AS affects human BK polyomavirus (BKPyV) and JC polyomavirus (JCPyV) replication in vitro [54,55]. Both viruses latently and asymptomatically infect the human host and are able to reactivate in immunosuppressed hosts, such as HIV-positive patients or transplant recipients.…”

Section: Artesunate and Other Virusesmentioning

confidence: 99%

The Use of Antimalarial Drugs against Viral Infection

et al. 2020

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In recent decades, drugs used to treat malaria infection have been shown to be beneficial for many other diseases, including viral infections. In particular, they have received special attention due to the lack of effective antiviral drugs against new emerging viruses (i.e., HIV, dengue virus, chikungunya virus, Ebola virus, etc.) or against classic infections due to drug-resistant viral strains (i.e., human cytomegalovirus). Here, we reviewed the in vitro/in vivo and clinical studies conducted to evaluate the antiviral activities of four classes of antimalarial drugs: Artemisinin derivatives, aryl-aminoalcohols, aminoquinolines, and antimicrobial drugs.

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Section: Artesunate and Other Virusesmentioning

confidence: 99%

The Use of Antimalarial Drugs against Viral Infection

et al. 2020

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“…Mitochondrial activity was measured at 72 hpt in the same wells, after incubation for 3 h with resazurin, by the colorimetric measurement of resazurin reduction using the TOX8 resazurin-based in vitro toxicology assay (Sigma) according to the manufacturer's instructions. As an alternative measure of metabolic activity, the total ATP content of the cells was measured at 72 hpt using the CellTiterGlo luminescent cell viability assay (Promega) as described earlier (35). To assess the cytotoxic properties of BCV, the semikinetic CellTox Green cytotoxicity assay was used, and fluorescence was measured at 0.5, 24, 48, and 72 hpt using the Tecan Infinite F200PRO reader (Tecan) as previously described (35).…”

Section: Methodsmentioning

confidence: 99%

“…As an alternative measure of metabolic activity, the total ATP content of the cells was measured at 72 hpt using the CellTiterGlo luminescent cell viability assay (Promega) as described earlier (35). To assess the cytotoxic properties of BCV, the semikinetic CellTox Green cytotoxicity assay was used, and fluorescence was measured at 0.5, 24, 48, and 72 hpt using the Tecan Infinite F200PRO reader (Tecan) as previously described (35).…”

Section: Methodsmentioning

confidence: 99%

Brincidofovir (CMX001) Inhibits BK Polyomavirus Replication in Primary Human Urothelial Cells

Tylden

Hirsch

Rinaldo

2015

Antimicrob Agents Chemother

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e BK polyomavirus (BKPyV)-associated hemorrhagic cystitis (PyVHC) complicates 5 to 15% of allogeneic hematopoietic stem cell transplantations. Targeted antivirals are still unavailable. Brincidofovir (BCV; previously CMX001) has shown inhibitory activity against diverse viruses, including BKPyV in a primary human renal tubule cell culture model of polyomavirus-associated nephropathy. We investigated the effects of BCV in BKPyV-infected and uninfected primary human urothelial cells (HUCs), the target cells of BKPyV in PyVHC. The BCV concentrations causing 50 and 90% reductions (EC 50 and EC 90 ) in the number of intracellular BKPyV genome equivalents per cell (icBKPyV) were 0.27 M and 0.59 M, respectively. At 0.63 M, BCV reduced viral late gene expression by 90% and halted progeny release. Preinfection treatment for only 24 h reduced icBKPyV similarly to treatment from 2 to 72 h postinfection, while combined pre-and postinfection treatment suppressed icBKPyV completely. After investigating BCV's effects on HUC viability, mean selectivity indices at 50 and 90% inhibition (SI 50 and SI 90 ) calculated for cellular DNA replication were 2.7 and 2.9, respectively, those for mitochondrial activity were 8.9 and 10.4, those for total ATP were 8.6 and 8.2, and those for membrane integrity were 25.9 and 16.7. The antiviral and cytostatic effects, but less so the cytotoxic effects, were inversely related to cell density. The cytotoxic effects at concentrations of >10 M were rapid and likely related to BCV's lipid moiety. After carefully defining the antiviral, cytostatic, and cytotoxic properties of BCV in HUCs, we conclude that a preemptive or prophylactic approach in PyVHC is likely to give the best results.T he ubiquitous and usually quiescent BK polyomavirus (BKPyV) causes polyomavirus-associated nephropathy (PyVAN) and hemorrhagic cystitis (PyVHC) following kidney and hematopoietic stem cell transplantation (HSCT), respectively (1).PyVHC afflicts 5 to 15% of HSCT patients after engraftment (2-5). The pathogenesis of PyVHC is incompletely characterized but is believed to involve initial iatrogenic damage to the bladder mucosa during pretransplantation conditioning, which is subsequently aggravated by lytic BKPyV replication in urothelial cells in the absence of immune surveillance. This leads to exposure of both viral and host epitopes to the foreign, engrafting lymphoid cells and may contribute to graft-versus-host disease (GVHD) (6-10). Inflammation and the resultant denudation of the urothelium cause hemorrhagic cystitis ranging from microhematuria to macrohematuria, clot-related urinary retention, and postrenal failure (reviewed in reference 5).PyVAN occurs in transplanted kidneys in 1 to 10% of recipients and often results in graft loss via a combination of lytic and inflammatory destruction of the renal parenchyma (2, 5). The initial reactivation signal is unknown, but mathematical modeling supports initial reactivation in the tubular epithelial compartment, followed by viral efflux with amplification in the uroth...

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“…78 Furthermore, a definitive demonstration of the in vivo efficacy of these drugs is still lacking and for some of them is weakly supported by some case reports. 79 Retro-2cycl and brefeldin A are able to interfere with viral replication by inhibiting retrograde transport of JCV to the endoplasmic reticulum in vitro, while no in vivo data are available so far. Nucleoside analog cytarabine; nucleotide analogs cidofovir and brincidofovir; small molecules like ganciclovir, topotecan, and leflunomide; the antimalarial drug mefloquine; Poly (ADP-ribose) polymerase inhibitors; the protein kinase inhibitor imatinib; and siRNA Ag122 (which targets JCV agnoprotein) have shown anti-JCV activity in vitro, by inhibiting viral DNA replication.…”

Section: Pml Therapymentioning

confidence: 99%

“…Clinical studies are needed to demonstrate the in vivo antiviral efficacy of artesunate. 79 Furthermore, several drugs have been tested in clinical studies, for their anti-JCV potential activity during AIDSrelated PML. In one Phase II clinical trial, HIV-positive patients with PML were randomly assigned to three different arms: treatment with cART alone, cART in combination with either intravenous or intrathecal cytarabine.…”

Section: Pml Therapymentioning

confidence: 99%