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At least 1,423 records · Page 79Linked to original sources
PubMed2001

Hepatitis C virus replication is directly inhibited by IFN-alpha in a full-length binary expression system.

Hepatitis C virus (HCV) is a leading cause of chronic hepatitis, cirrhosis, and hepatocellular carcinoma. The absence of culture systems permissive for HCV replication has presented a major bottleneck to antiviral development. We sought to recapitulate the early steps in the life cycle of HCV by means of DNA-based expression of viral genomic sequences. Here we report expression of replicating HCV RNA by using a, to our knowledge, novel binary expression system in which cells were transfected with a T7 polymerase-driven full-length HCV cDNA plasmid containing a cis-acting hepatitis Delta ribozyme to control 3' cleavage, and infected with vaccinia-T7 polymerase. HCV genomic and replicative strand synthesis, in addition to protein synthesis, was detectable and depended on full-length HCV sequences. Moreover, the system was capable of generating HCV RNA quasispecies, consistent with the action of the low-fidelity HCV NS5B RNA polymerase. IFN-alpha, but not ribavirin, directly inhibited the viral replicative cycle in these cells, identifying the virus itself and not solely the immune system as a direct target of IFN action. The availability of a cell-based test for viral replication will facilitate screening of inhibitory compounds, analysis of IFN-resistance mechanisms, and analysis of virus-host cell interactions.

Amantadine↗
PubMed1997

Inhibitory activity of soyasaponin II on virus replication in vitro.

The antiviral activities of two saponins, soyasaponin I and II, isolated from soybean (Glycine max Merrill) were studied in vitro against herpes simplex virus type 1 (HSV-1). Soyasaponin II was more potent than soyasaponin I as shown by reduction of HSV-1 production. Soyasaponin II was also found to inhibit the replication of human cytomegalovirus, influenza virus, and human immunodeficiency virus type 1. The action was not due to inhibition of virus penetration and protein synthesis, but might involve a virucidal effect. When acyclovir and soyasaponin II were evaluated in combination for anti-HSV-1 activity, additive antiviral effects were observed for this virus.

Animals↗
PubMed1996

Thogoto and Dhori virus replication is blocked by inhibitors of cellular polymerase II activity but does not cause shutoff of host cell protein synthesis.

Tick-transmitted Thogoto and Dhori viruses share structural and genetic properties with the influenza viruses. Here, we compare different steps of their replication cycle in mammalian cells in comparison with influenza A virus. Viral antigens of both viruses accumulated in the nuclei of infected cells, suggesting a nuclear phase of viral replication. Furthermore, as observed with influenza viruses, transcription of Thogoto and Dhori viruses was inhibited by alpha-amanitin and actinomycin D, suggesting a dependence of viral transcription on cellular RNA polymerase II activity. In contrast to influenza viruses, Thogoto and Dhori virus infection did not lead to down-regulation of cellular protein synthesis indicating marked differences regarding the fate of infected cells.

3T3 Cells↗
PubMed2005

West Nile virus replication interferes with both poly(I:C)-induced interferon gene transcription and response to interferon treatment.

West Nile virus (WNV), the leading cause of viral encephalitis in the United States, is an arthropod-transmitted member of the family Flaviviridae. We have explored the interaction of this positive-strand RNA virus with signaling pathways involved in induction of the host's innate immune response. Phosphorylation of STAT-1 in response to interferon (IFN) treatment and the ability of IFN to establish an antiviral state were reduced in WNV replicon-bearing cell lines. Similarly, the activation of IRF3 and stimulation of IFN-beta transcription in response to the double-stranded RNA (dsRNA) mimetic poly(I:C) were inhibited in replicon-bearing and WNV-infected HeLa cells. In contrast, WNV replicons did not affect IRF3 activation by Sendai virus infection, suggesting that not all IRF3 activating pathways are inhibited by WNV. Taken together, these findings demonstrate that WNV replication in cultured cells interferes with both the response to IFN and synthesis of IFN-beta in response to dsRNA.

Active Transport, Cell Nucleus↗
PubMed1989

Inhibition of duck hepatitis B virus replication by 2',3'-dideoxycytidine. A potent inhibitor of reverse transcriptase.

The effect of 2',3'-dideoxycytidine, a potent antiviral agent, which, following anabolic phosphorylation, inhibits the reverse transcriptase of the human immunodeficiency virus in vitro, was assessed in 16 Pekin ducks chronically infected with the duck hepatitis B virus. Nine ducks were given 11 mg/m2 of dideoxycytidine intravenously every 6 h, and 7 ducks received no treatment. Serum duck hepatitis B virus deoxyribonucleic acid and deoxyribonucleic acid polymerase activity decreased in every duck treated with dideoxycytidine. The mean inhibition of deoxyribonucleic acid polymerase and duck hepatitis B virus deoxyribonucleic acid on the third day of treatment measured 64% (p less than 0.01) and 73% (p less than 0.01), respectively. The inhibition of deoxyribonucleic acid polymerase persisted after treatment was stopped, and 4 ducks continued to show greater than 50% inhibition 12 days after stopping treatment. Duck hepatitis B virus deoxyribonucleic acid, which was measured in total cellular deoxyribonucleic acid extracted from liver biopsy specimens obtained before and on the last day of treatment with dideoxycytidine, showed an average inhibition of 96% in 3 ducks treated with dideoxycytidine, but showed no decrease in the remaining 5 ducks. Thus, dideoxycytidine has potent antiviral activity against duck hepatitis B virus and warrants further evaluation as an antiviral agent in the treatment of chronic hepatitis B virus infection in humans.

Animals↗
PubMed1994

Effect of BV-araU and acyclovir on varicella-zoster virus replication with various length and timing of drug exposure.

We studied antiviral effects of 1-beta-D-arabinofuranosyl-5-[(E)-2-bromovinyl]uracil (BV-araU) and acyclovir against varicella-zoster virus (VZV) multiplication varying the length or timing of drug exposure. First, residual anti-VZV effect of drugs, exposed to cells for various periods followed by incubation in drug-free medium, was determined by the plaque inhibition assay. None of the drugs showed activity when removed within 24 hr of incubation. Weakened efficacy of BV-araU was seen in 2 days of treatment. When it was removed after 3 or 4 days, the ED50 was as low as that for cultures in which the drug was not removed. Still, plaque inhibition was not complete even at high concentrations. Acyclovir inhibited plaque formation only by 50% or less in 2 days of treatment. It gave a much higher ED50 in 3 days of treatment than that observed without drug removal. In the experiments, in which BV-araU was added to VZV-infected cells 1 day after infection, BV-araU immediately suppressed increase in the number of infective centers at a concentration of 0.001 microgram/ml, and reduced it at concentrations of 0.01 microgram/ml or higher. The reduction of infective centers was seen with a dose-dependent manner when added 2 or 3 days after infection. BV-araU stimulated the decrease in the number of infective centers when added 4 days after infection. This inhibitory effect of acyclovir was very weak. Microscopic observations supported the above results. BV-araU was still much superior to acyclovir in the anti-VZV effect when the length and timing of drug exposure were varied.

Acyclovir↗
PubMed2004

Inhibition of human immunodeficiency virus replication by a dual CCR5/CXCR4 antagonist.

Here we report that the N-pyridinylmethyl cyclam analog AMD3451 has antiviral activity against a wide variety of R5, R5/X4, and X4 strains of human immunodeficiency virus type 1 (HIV-1) and HIV-2 (50% inhibitory concentration [IC(50)] ranging from 1.2 to 26.5 microM) in various T-cell lines, CCR5- or CXCR4-transfected cells, peripheral blood mononuclear cells (PBMCs), and monocytes/macrophages. AMD3451 also inhibited R5, R5/X4, and X4 HIV-1 primary clinical isolates in PBMCs (IC(50), 1.8 to 7.3 microM). A PCR-based viral entry assay revealed that AMD3451 blocks R5 and X4 HIV-1 infection at the virus entry stage. AMD3451 dose-dependently inhibited the intracellular Ca(2+) signaling induced by the CXCR4 ligand CXCL12 in T-lymphocytic cells and in CXCR4-transfected cells, as well as the Ca(2+) flux induced by the CCR5 ligands CCL5, CCL3, and CCL4 in CCR5-transfected cells. The compound did not interfere with chemokine-induced Ca(2+) signaling through CCR1, CCR2, CCR3, CCR4, CCR6, CCR9, or CXCR3 and did not induce intracellular Ca(2+) signaling by itself at concentrations up to 400 microM. In freshly isolated monocytes, AMD3451 inhibited the Ca(2+) flux induced by CXCL12 and CCL4 but not that induced by CCL2, CCL3, CCL5, and CCL7. The CXCL12- and CCL3-induced chemotaxis was also dose-dependently inhibited by AMD3451. Furthermore, AMD3451 inhibited CXCL12- and CCL3L1-induced endocytosis in CXCR4- and CCR5-transfected cells. AMD3451, in contrast to the specific CXCR4 antagonist AMD3100, did not inhibit but enhanced the binding of several anti-CXCR4 monoclonal antibodies (such as clone 12G5) at the cell surface, pointing to a different interaction with CXCR4. AMD3451 is the first low-molecular-weight anti-HIV agent with selective HIV coreceptor, CCR5 and CXCR4, interaction.

Anti-HIV Agents↗