Check out our New Publishers' Select for Free Articles

Antiviral Research (v.68, #2)

Prelim II: Editorial Board (pp. ii).

Prelim V: Instructions to Authors (pp. v-vii).

Inside Back Cover: Notes to Authors (pp. co3).

Broad-spectrum inhibitor of viruses in the Flaviviridae family by Joshua O. Ojwang; Shoukath Ali; Donald F. Smee; John D. Morrey; Craig D. Shimasaki; Robert W. Sidwell (pp. 49-55).

The viruses in the Flaviviridae family have been associated with human and animal diseases. In this report, we demonstrate that compound 2-amino-8-(β-d-ribofuranosyl) imidazo [1,2-a]-s-triazine-4-one (ZX-2401) was capable of inhibiting the production in culture of at least five members of the Flaviviridae family with minimal cytotoxicity. This compound inhibited yellow fever virus, dengue virus, bovine viral diarrhea virus, banzi virus and West Nile virus with EC₅₀ of 10, 10, 5, 5 and 3μg/ml, respectively, and the CC₅₀ in these experiments were greater than 1000μg/ml. The activity of ZX-2401 is comparable to or better than the control drugs in these studies and was not affected by MOI variation. In addition, ZX-2401 inhibited HCV replication in a dose response fashion in the replicon assay system. Furthermore, ZX-2401 exhibited a synergistic antiviral activity in combination with IFN in tissue culture. The data described herein suggest that ZX-2401 is a broad-spectrum inhibitor of the RNA viruses, which has merit for development of treatments for the emerging infections caused by the viruses in the Flaviviridae family.

Keywords: Antivirals; Flavivirus; West Nile virus; Hepatitis C virus; Nucleoside analog; Broad-spectrum inhibitor

Viral and cellular gene transcription in fibroblasts infected with small plaque mutants of varicella-zoster virus by Jeremy O. Jones; Ann M. Arvin (pp. 56-65).

Varicella-zoster virus (VZV) is an alphaherpesvirus that causes varicella and herpes zoster. In these experiments, cDNA corresponding to 69 VZV open reading frames was added to 42K human cDNA microarrays and used to examine viral as well as cellular gene transcription concurrently in fibroblasts infected with two genetically distinct small plaque VZV mutants, rOka/ORF63rev[T171] and rOkaΔgI. rOka/ORF63rev[T171] has a point mutation in ORF63, which encodes the immediate early regulatory protein, IE63, and rOkaΔgI has a deletion of ORF67, encoding glycoprotein I (gI). rOka/ORF63rev[T171] was deficient in the transcription of several viral genes compared to the recombinant rOka control virus. Deletion of ORF67 had minimal effects on viral gene transcription. Effects of rOka/ORF63rev[T171] and rOkaΔgI on host cell gene transcription were similar to the rOka control, but a few host cell genes were regulated differently in rOkaΔgI-infected cells. Infection of fibroblasts with intact or small plaque VZV mutants was associated with down-regulation of NF-κB and interferon responsive genes, down-regulation of TGF-β responsive genes accompanied by reduced amounts of fibrotic/wound healing response genes (e.g. collagens, follistatin) and activation of cellular proliferation genes, and alteration of neuronal growth markers, as well as cellular genes encoding proteins important in protein and vesicle trafficking. These observations suggest that replication of VZV small plaque mutant viruses and intact VZV have similar consequences for host cell gene transcription in infected cells, and that the small plaque phenotype in these mutants reflects deficiencies in viral gene expression.

Keywords: Varicella-zoster virus; Fibroblast; Gene transcription

Antiviral effect of catechins in green tea on influenza virus by Jae-Min Song; Kwang-Hee Lee; Baik-Lin Seong (pp. 66-74).

Polyphenolic compound catechins ((−)-epigallocatechin gallate (EGCG), (−)-epicatechin gallate (ECG) and (−)-epigallocatechin (EGC)) from green tea were evaluated for their ability to inhibit influenza virus replication in cell culture and for potentially direct virucidal effect. Among the test compounds, the EGCG and ECG were found to be potent inhibitors of influenza virus replication in MDCK cell culture and this effect was observed in all influenza virus subtypes tested, including A/H1N1, A/H3N2 and B virus. The 50% effective inhibition concentration (EC₅₀) of EGCG, ECG, and EGC for influenza A virus were 22–28, 22–40 and 309–318μM, respectively. EGCG and ECG exhibited hemagglutination inhibition activity, EGCG being more effective. However, the sensitivity in hemagglutination inhibition was widely different among three different subtypes of influenza viruses tested. Quantitative RT-PCR analysis revealed that, at high concentration, EGCG and ECG also suppressed viral RNA synthesis in MDCK cells whereas EGC failed to show similar effect. Similarly, EGCG and ECG inhibited the neuraminidase activity more effectively than the EGC. The results show that the 3-galloyl group of catechin skeleton plays an important role on the observed antiviral activity, whereas the 5′-OH at the trihydroxy benzyl moiety at 2-position plays a minor role. The results, along with the HA type-specific effect, suggest that the antiviral effect of catechins on influenza virus is mediated not only by specific interaction with HA, but altering the physical properties of viral membrane.

Keywords: Influenza virus; Catechins; Green tea; EGCG; ECG; Hemagglutination

Effect of artemisinin/artesunate as inhibitors of hepatitis B virus production in an “in vitro�? replicative system by Marta R. Romero; Thomas Efferth; Maria A. Serrano; Beatriz Casta�o; Rocio I.R. Macias; Oscar Briz; Jose J.G. Marin (pp. 75-83).

The antiviral effect against hepatitis B virus (HBV) of artemisinin, its derivative artesunate and other compounds highly purified from traditional Chinese medicine remedies, were investigated. HBV production by permanently transfected HepG2 2.2.15 cells was determined by measuring the release of surface protein (HBsAg) and HBV-DNA after drug exposure (0.01–100μM) for 21 days. The forms of HBV-DNA released were investigated by Southern-blotting. Neutral Red retention test was used to evaluate drug-induced toxicity on host cells. The compounds were classified according to their potential interest as follows: (i) none: they had no effect on viral production (daidzein, daidzin, isonardosinon, nardofuran, nardosinon, tetrahydronardosinon and quercetin); (ii) low: they were able to markedly reduce viral production, but also induced toxicity on host cells (berberine and tannic acid) or they had no toxic effect on host cells but only had a moderate ability to reduce viral production (curcumin, baicalein, baicalin, bufalin, diallyl disulphide, glycyrrhizic acid and puerarin); (iii) high: they induced strong inhibition of viral production at concentrations at which host cell viability was not affected (artemisinin and artesunate). Moreover, artesunate in conjunction with lamivudine had synergic anti-HBV effects, which warrants further evaluation of artemisinin/artesunate as antiviral agents against HBV infection.

Keywords: Abbreviations; DMSO; dimethylsulfoxide; HBV; hepatitis B virus; HBsAg; HBV surface antigen; NR; Neutral Red; PCR; polymerase chain reaction; QPCR; quantitative real-time PCR; Ct; QPCR, cycle at which the arbitrary fluorescence threshold is reached; TCM; traditional Chinese medicineArtemisinin; Artesunate; Curcumin; Traditional Chinese medicine; Hepatitis B

Methylene blue photoinactivation abolishes West Nile virus infectivity in vivo by James F. Papin; Robert A. Floyd; Dirk P. Dittmer (pp. 84-87).

The prevalence of West Nile virus (WNV) infections and associated morbidity has accelerated in recent years. Of particular concern is the recent demonstration that this virus can be transmitted by blood products and can cause severe illness and mortality in transfusion recipients. We have evaluated methylene blue (MB)+light as a safe and cost-effective means to inactivate WNV in vitro. This regimen inactivated WNV with an IC₅₀ of 0.10μM. Up to 10⁷pfu/ml of WNV could be inactivated by MB+light with no residual infectivity. MB+light inactivated three primary WNV isolates from the years 1999, 2002 and 2003 and prevented mortality in a murine model for WNV infection. Since MB is already approved for human use at a dose of 100mg/kg/day, we conjecture that MB+light treatment of blood products for high-risk patients will be efficacious and suitable for use in resource-limited settings.

Keywords: Methylene blue; West Nile virus

Antiviral mode of action of a synthetic brassinosteroid against Junin virus replication by Viviana Castilla; Mariano Larz�bal; Natalia Aguirre Sgalippa; M�nica B. Wachsman; Celia E. Coto (pp. 88-95).

The antiviral mode of action of the synthetic brassinosteroid (22S,23S)-3β-bromo-5α,22,23-trihydroxystigmastan-6-one (6b) against Junin virus replication in Vero cells was investigated. Time-related experiments showed that6b mainly affects an early event of virus growth cycle. Neither adsorption nor internalization of viral particles was the target of the inhibitory action. The analysis of the effect of6b on viral RNA synthesis demonstrated that the presence of the compound adversely affects virus RNA replication by preventing the synthesis of full length antigenomic RNA. Although6b was most effective the earlier it was added to the cells after infection with JV, a high level of inhibition of JV yield and fusion activity of newly synthesized viral glycoproteins was still detected when the compound was present during the last hours of infection. Therefore, we cannot rule out an inhibitory action of6b on later events of JV replicative cycle.

Keywords: Arenavirus; Hemorrhagic fever virus; Brassinosteroid; Antiviral activity

Inhibition of CCR5-mediated infection by diverse R5 and R5X4 HIV and SIV isolates using novel small molecule inhibitors of CCR5: Effects of viral diversity, target cell and receptor density by Samantha Willey; Paul J. Peters; W. Matthew Sullivan; Patrick Dorr; Manos Perros; Paul R. Clapham (pp. 96-108).

Highly active anti-retroviral therapy (HAART) has been very effective in reducing viral loads in human immunodeficiency virus (HIV)-1 patients. However, current therapies carry detrimental side effects, require complex drug regimes and are threatened by the emergence of drug-resistant variants. There is an urgent need for new anti-HIV drugs that target different stages of the replication cycle. Several synthetic small organic molecules that inhibit HIV infection by binding to the CCR5 coreceptor without causing cell activation have already been reported. Here, we have exploited a series of CCR5 antagonists to investigate their effects on diverse HIV and the simian counterpart (SIV) isolates for infection of a variety of cell types via different concentrations of cell surface CCR5. These inhibitors show no cross-reactivity against alternative HIV coreceptors including CCR3, CCR8, GPR1, APJ, CXCR4 and CXCR6. They are able to inhibit a diverse range of R5 and R5X4 HIV-1 isolates as well as HIV-2 and SIV strains. Inhibition was observed in cell lines as well as primary PBMCs and macrophages. The extent of inhibition was dependent on cell type and on cell surface CCR5 concentration. Our results underscore the potential of CCR5 inhibitors for clinical development.

Keywords: HIV coreceptors; HAART; CCR5; Coreceptor inhibitor

Sections

Personal tools

Antiviral Research (v.68, #2)

Sections

Personal tools

Local resources

Antiviral Research (v.68, #2)