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At least 1,153 records · Page 64Linked to original sources
PubMed2005

Inhibitory effect of cyclosporine A on hepatitis B virus replication in vitro and its possible mechanisms.

BACKGROUND: Hepatitis B related end-stage liver disease is recently acknowledged as one of the main indications for orthotopic liver transplantation (OLT). However, the high recurrence rate of hepatitis B virus infection following transplantation is regarded as a major factor affecting the long-term survival of transplant recipients especially in China. Cyclosporine A (CsA), which is routinely used to prevent the allograft rejection, is reported to have the inhibitory activity on hepatitis B virus (HBV) replication in vitro. In this paper, we review the inhibitory effect and its possible mechanisms of CsA on HBV replication in vitro. DATA RESOURCES: An English-language literature search was conducted using MEDLINE (1990-2004) on cyclosporine A, hepatitis B virus, mitochondria, calcium and other related reports and review articles. RESULTS: Hepatitis B x protein (HBx) is essential to HBV replication. The cytosolic calcium signaling mediated by mitochondria and the Src kinase pathway were involved during HBx activation of HBV replication. CsA inhibits the HBV replication in vitro by its binding to mitochondrial cyclophilin D, then blocking the mitochondria-mediated cytosolic calcium signaling. The derivates of CsA also have the HBV replication inhibitory effect in vitro. CONCLUSIONS: By interacting with mitochondria, preventing the release of intramitochondrial calcium, and then blocking the cytosolic calcium signaling, CsA inhibits the HBV replication in vitro. The derivates of CsA also have this activity.

Calcium Signaling↗
PubMed1989

Characterization of the early steps of herpes simplex virus replication in interferon-treated human cells.

Interferon (IFN) was shown to inhibit herpes simplex virus type 1 (HSV-1) replication at the transcription of the immediate early (alpha) genes. This apparent inhibition could be due to a direct effect on viral transcription or on one of the preceding steps of infection, i.e., penetration and uncoating. In the present study, we analyze the effects of IFN on the very early steps of HSV-1 infection in HEp-2 human cells. Analysis of the parental HSV-1 viral DNA accumulated in the infected cell nuclei indicated that viral DNA penetration, migration to the nuclei, and stability were not affected by IFN treatment. To analyze the effect of IFN on the uncoating of the parental HSV-1 DNA following infection, we developed a technique based on DNase I sensitivity of the infecting viral DNA genome. Within 1 h of infection, the parental viral DNA became sensitive to DNase I digestion. HSV-1 DNA in the nuclei of both control and IFN-treated cells was equally sensitive to DNase I digestion, suggesting that IFN's mode of action was unrelated to the uncoating of HSV-1 virions. Because IFN does not affect the events in the HSV-1 lytic cycle prior to the onset of the immediate-early gene transcription, it appears that IFN exerts a direct effect on this process.

Cells, Cultured↗
PubMed1997

Matching antibody class with pathogen type and portal of entry: cognate mechanisms regulate local isotype expression patterns in lymph nodes draining the respiratory tract of mice inoculated with respiratory viruses, according to virus replication competence and site of inoculation.

Intranasal deposition of Sendai virus (SV) in C57BL/6 mice provokes an Ab-forming cell (AFC) reaction in mediastinal (MLN) and cervical lymph nodes (CLN), which drain the lungs and upper respiratory tract, respectively. While the majority of AFC elicited by infectious SV at both sites produced IgG, the CLN response to SV rendered inactive in replication was restricted almost entirely to IgA, although isotype switching in mediastinal continued to be skewed heavily to IgG. However, in vitro restimulation of the accompanying virus-specific T cell populations from the two sites did not reveal any significant difference in lymphokine output, and isotype expression was not altered substantially in mice lacking IL-4 or IL-6 genes. To dissociate the response to specific Ags from the inflammatory reaction to viral infection, we examined the response to inactivated SV in the face of infection with influenza virus A/HKx31. The magnitude and IgA dominance of the anti-SV AFC population in the CLN were unaffected by a simultaneous, vigorous, IgG-dominated CLN anti-influenza reaction. Evidently, the characteristics of this antiviral response are determined primarily by cognate interactions. Moreover, the IgA bias of the CLN AFC response to inactivated SV was observed only when the virus was delivered intranasally: injection under the epidermis of the cheek, a site that has a lymphatic drainage into the CLN, resulted in an IgG-dominated CLN AFC reaction, lacking IgA. The site of deposition of a vaccine can thus have more influence on the pattern of isotypes induced than the site at which the immune response is initiated.

Animals↗
PubMed2006

Redox modulation of the hepatitis C virus replication complex is calcium dependent.

Reactive species and perturbation of the redox balance have been implicated in the pathogenesis of many viral diseases, including hepatitis C. Previously, we made a surprising discovery that concentrations of H(2)O(2) that are nontoxic to host cells disrupted the hepatitis C virus (HCV) replication complex (RC) in Huh7 human hepatoma cells in a manner that suggested signaling. Here, we show that H(2)O(2) and interferon-gamma have comparable effects on the HCV subgenomic and genomic RNA replication in Huh7 cells. H(2)O(2) induced a gradual rise in the intracellular calcium concentration ([Ca(2+)](i)). Both rapid and sustained suppression of HCV RNA replication by H(2)O(2) depended on this calcium elevation. The peroxide-induced [Ca(2+)](i) elevation was independent of extracellular calcium and derived, at least in part, from the endoplasmic reticulum. Likewise, the suppression of the HCV RC by H(2)O(2) was independent of extracellular calcium but required an intracellular calcium source. Other agents that elevated [Ca(2+)](i) could also suppress the HCV RC, suggesting that calcium elevation might be sufficient to suppress HCV RNA replication. In conclusion, oxidants may modulate the HCV RC through calcium. Effects on the infectivity and the morphogenesis of HCV remain to be determined. These findings suggest possible regulatory roles for redox and calcium signaling during viral infections.

Adenosine Triphosphate↗
PubMedDate not supplied

Inhibition of influenza virus replication by phosphorothioate and liposomally endocapsulated oligonucleotides.

We have demonstrated that antisense phosphorothioate oligonucleotides (S-ODNs) inhibit influenza virus A replication in MDCK cells. Phosphorothioate and liposomally encapsulated oligonucleotides with two target sites (PB1 and PB2) were synthesized and tested for virus-induced cytopathogenicity effects by a MTT assay using MDCK cells. The liposomally encapsulated S-ODNs complementary to the sites of the PB2-AUG initiation codon showed highly inhibitory effects. On the other hand, the inhibitory effect of the liposomally encapsulated S-ODNs targeted to PB1 was considerably decreased in comparison with the PB2 target sites. The liposomally encapsulated oligonucleotides exhibited higher inhibitory activity than the free oligonucleotides. The activities of the modified oligonucleotides are effectively enhanced by using the liposomal carrier.

Antiviral Agents↗
PubMed2004

Role of human immunodeficiency virus type 1 matrix phosphorylation in an early postentry step of virus replication.

The matrix domain (MA) is important for targeting of human immunodeficiency virus type 1 Gag assembly to the plasma membrane, envelope incorporation into virions, preintegration complex import into the nucleus, and nuclear export of viral RNA. Myristylation and phosphorylation are key regulatory events for MA function. Previous studies have indicated that MA phosphorylation at serine (Ser) residues is important for viral replication. This study defines the molecular mechanisms of virus particle assembly and infectivity through a detailed study of the role of MA serine phosphorylation. We show that the combined mutation of Ser residues at positions 9, 67, 72, and 77 impairs viral infectivity in dividing and nondividing cells, although the assembly of these Ser mutant viruses is comparable to that of wild-type virus. This defect can be rescued by pseudotyping these mutant viruses with vesicular stomatitis virus G protein, suggesting that these serine residues are critical in an early postentry step of viral infection. The phosphorylation level of MA in defective mutant viruses was severely reduced compared to that of the wild type, suggesting that phosphorylation of Ser-9, -67, -72, and -77 is important for an early postentry step during virus infection.

Cell Division↗
PubMed1989

Involvement of prostaglandin-induced proteins in the inhibition of herpes simplex virus replication.

Cyclopentenone prostaglandin (PG), delta7-PGA1 was found to induce several polypeptides in human embryonic fibroblast (HEF) cells which were noticed to be dose-related and appeared after 1 h of treatment with a peak at around 5 h and gradual disappearance after 12 h. PG-induced proteins were almost identical in terms of molecular weights with those induced by heat-shock at 42 degrees C. Regarding the mechanism of inhibition of herpes simplex virus (HSV) replication by PG in cell culture, dot blot hybridization has revealed that the level of immediate early (IE) mRNA of the virus was reduced after PG treatment with time dependence. And this delayed inhibitory effect of delta7-PGA1 on HSV was shown to be associated with the production and accumulation of the induced polypeptides.

Cells, Cultured↗
PubMed2004

Cleavage between replicase proteins p28 and p65 of mouse hepatitis virus is not required for virus replication.

The p28 and p65 proteins of mouse hepatitis virus (MHV) are the most amino-terminal protein domains of the replicase polyprotein. Cleavage between p28 and p65 has been shown to occur in vitro at cleavage site 1 (CS1), (247)Gly downward arrow Val(248), in the polyprotein. Although critical residues for CS1 cleavage have been mapped in vitro, the requirements for cleavage have not been studied in infected cells. To define the determinants of CS1 cleavage and the role of processing at this site during MHV replication, mutations and deletions were engineered in the replicase polyprotein at CS1. Mutations predicted to allow cleavage at CS1 yielded viable virus that grew to wild-type MHV titers and showed normal expression and processing of p28 and p65. Mutant viruses containing predicted noncleaving mutations or a CS1 deletion were also viable but demonstrated delayed growth kinetics, reduced peak titers, decreased RNA synthesis, and small plaques compared to wild-type controls. No p28 or p65 was detected in cells infected with predicted noncleaving CS1 mutants or the CS1 deletion mutant; however, a new protein of 93 kDa was detected. All introduced mutations and the deletion were retained during repeated virus passages in culture, and no phenotypic reversion was observed. The results of this study demonstrate that cleavage between p28 and p65 at CS1 is not required for MHV replication. However, proteolytic separation of p28 from p65 is necessary for optimal RNA synthesis and virus growth, suggesting important roles for these proteins in the formation or function of viral replication complexes.

Base Sequence↗
PubMed1999

Inhibition of influenza virus replication by nitric oxide.

Nitric oxide (NO) has been shown to contribute to the pathogenesis of influenza virus-induced pneumonia in mouse models. Here we show that replication of influenza A and B viruses in Mabin Darby canine kidney cells is severely impaired by the NO donor, S-nitroso-N-acetylpenicillamine. Reduction of productively infected cells and virus production proved to correlate with inhibition of viral RNA synthesis, indicating that NO affects an early step in the replication cycle of influenza viruses.

Animals↗
PubMed2004

Helper-dependent adenoviral vector-mediated delivery of woodchuck-specific genes for alpha interferon (IFN-alpha) and IFN-gamma: IFN-alpha but not IFN-gamma reduces woodchuck hepatitis virus replication in chronic infection in vivo.

Alpha interferon (IFN-alpha) and IFN-gamma are able to suppress hepadnavirus replication. The intrahepatic expression of high levels of IFN may enhance the antiviral activity. We investigated the effects of woodchuck-specific IFN-alpha (wIFN-alpha) and IFN-gamma(wIFN-gamma) on woodchuck hepatitis virus (WHV) replication in vivo by helper-dependent adenoviral (HD-Ad) vector-mediated gene transfer. The expression of biologically active IFNs was demonstrated in vitro after transduction of woodchuck cells with HD-Ad vectors encoding wIFN-alpha (HD-AdwIFN-alpha) or wIFN-gamma (HD-AdwIFN-gamma). The transduction efficacy of the HD-Ad vector in woodchuck liver in vivo was tested with a vector expressing green fluorescence protein (GFP). Immunohistochemical staining of liver samples on day 5 after injection showed expression of GFP in a high percentage of liver cells surrounding the central vein. The transduction of livers of WHV carriers in vivo with HD-AdwIFN-alpha or HD-AdwIFN-gamma induced levels of biologically active IFN, which could be measured in the sera of these animals. Expression of wIFN-alpha in the liver reduced intrahepatic WHV replication and WHV DNA in sera of about 1 log step in two of two woodchucks. Transduction with HD-AdwIFN-gamma, however, reduced WHV replicative intermediates only slightly in two of three animals, which was not accompanied with significant changes in the WHV DNA in sera. We demonstrated for the first time the successful HD-Ad vector-mediated transfer of genes for IFN-alpha and IFN-gamma in vivo and timely limited reduction of WHV replication by wIFN-alpha, but not by wIFN-gamma.

Adenoviridae↗
PubMed2001

A single amino acid in the reverse transcriptase domain of hepatitis B virus affects virus replication efficiency.

To explore functional domains in the hepatitis B virus (HBV) polymerase, two naturally occurring HBV isolates (56 and 2-18) with 98.7% nucleic acid sequence homology but different replication efficiencies were studied. After transfection into HepG2 cells, HBV DNA isolated from intracellular virus core particles was much higher in 56-transfected cells than in cells transfected with 2-18. The structural basis for the difference in replication efficiency between these two isolates was studied by functional domain gene substitution. The complete polymerase (P) gene and its gene segments coding for the terminal protein (TP), spacer (SP), reverse transcriptase (RT), and RNase H in 2-18 were separately replaced with their counterparts from 56 to construct full-length chimeric genomes. Cell transfection analysis revealed that substitution of the complete P gene of 2-18 with the P gene from 56 slightly enhanced viral replication. The only chimeric genome that regained the high replication efficiency of the original 56 isolate was the one with substitution of the RT gene of 2-18 with that from 56. Within the RT region, amino acid differences between isolates 2-18 and 56 were located at positions 617 (methionine versus leucine), 652 (serine versus proline), and 682 (valine versus leucine). Point mutation identified amino acid 652 as being responsible for the difference in replication efficiency. Homologous modeling studies of the HBV RT domain suggest that the mutation of residue 652 from proline to serine might affect the conformation of HBV RT which interacts with the template-primer, leading to impaired polymerase activity.

Amino Acids↗
PubMed1996

(-)-cis-5-fluoro-1-[2-(hydroxymethyl)-1,3-oxathiolan-5-yl]cytosine (524W91) inhibits hepatitis B virus replication in primary human hepatocytes.

The anti-hepatitis B virus (HBV) activity of (-)-cis-5-fluoro-1-[2-(hydroxymethyl)-1,3-oxathiolan-5-yl]cytosine (524W91) in cultures of primary human hepatocytes was examined. 524W91 was anabolized to the active 5'-triphosphate in these cells. HBV replication was equally inhibited in cultures incubated with 524W91 when the drug was added 24 h preinfection, at infection, or 24 h postinfection. 524W91 inhibited HBV replication by 50% at less than 20 nM in human hepatocytes.

Antiviral Agents↗
PubMed2002

Cleavage at the furin consensus sequence RAR/KR(109) and presence of the intervening peptide of the respiratory syncytial virus fusion protein are dispensable for virus replication in cell culture.

Proteolytic processing of the respiratory syncytial virus F (fusion) protein results in the generation of the disulfide-linked subunits F1 and F2 and in the release of pep27, a glycopeptide originally located between the two furin cleavage sites FCS-1 (RKRR(136)) and FCS-2 (RAR/KR(109)). We made use of reverse genetics to study the importance of FCS-2 and of pep27 for BRSV replication in cell culture. Replacement of FCS-2 in the F protein of recombinant viruses by either of the sequences NANR(109), RANN(109) or SANN(109), respectively, abolished proteolytic processing at this position, whereas the cleavage of FCS-1 was not affected. All mutants replicated in calf kidney and Vero cells in the absence of exogenous trypsin, although somewhat higher titers of BRSV containing the NANR(109) or the RANN(109) motif were achieved in the presence of trypsin. The virus mutants showed a reduced cytopathic effect which was lowest in the case of the SANN(109) mutant. These findings demonstrate that cleavage at FCS-2 is dispensable for replication of respiratory syncytial virus in cell culture. A deletion mutant containing FCS-1 but lacking FCS-2 and most of pep27 replicated in cell culture as efficiently as the parental virus, indicating that this domain of the F protein is not essential for virus maturation and infectivity.

Amino Acid Sequence↗
PubMed1988

The action of recombinant bovine interferons on influenza virus replication correlates with the induction of two Mx-related proteins in bovine cells.

Recombinant bovine interferon-alpha and -gamma differ in their action against influenza virus on bovine cells. Bovine IFN-alpha severely impairs early protein synthesis and replication of influenza virus in bovine cells in contrast to bovine IFN-gamma which fails to induce an antiviral state against influenza virus. Otherwise the IFN system seems to function normally in bovine cells since both bovine IFN-alpha and -gamma induce an antiviral state against vesicular stomatitis virus. The establishment of the specific antiviral state against influenza virus correlates with the induction by bovine IFN-alpha, but not -gamma, of two cytoplasmic proteins related to the IFN-induced mouse protein Mx involved in the mechanism of resistance of mice to influenza virus infection. This study suggests that bovines possess a system for resistance to influenza virus similar to the mouse Mx system.

Animals↗
PubMed1999

Virus replication begins in dendritic cells during the transmission of HIV-1 from mature dendritic cells to T cells.

BACKGROUND: To initiate immunity, dendritic cells (DCs) capture antigens or viruses at body surfaces, undergo maturation to express T-cell costimulatory molecules, and then migrate to lymphoid organs. DCs at body surfaces can capture human immunodeficiency virus 1 (HIV-1), but mature DCs do not support replication of the virus unless T cells are added. The initial site for HIV-1 replication remains unknown and it is unclear whether replication can take place in DCs or whether the virus must first be transmitted from DCs to T cells. RESULTS: We generated mature DCs from monocyte precursors. Upon infection with HIV-1, reverse transcription was completed only when T cells were added. When the reverse transcriptase inhibitor azidothymidine was added to the DCs during exposure to HIV-1, the DCs remained fully infectious, as long as the drug was removed just before culturing the DCs with T cells. HIV-1 variants that were engineered to undergo only one cycle of replication were able to infect DCs and replicate once in these cells. When T cells were added, newly produced HIV-1 Gag protein was exclusively localized to the DCs. With wild-type virus, subsequent rounds of replication took place in T cells. Soluble CD40 ligand (CD40L) and CD40L-transfected fibroblasts stimulated HIV-1 replication in purified mature DCs. CONCLUSIONS: Mature DCs provide a drug-resistant reservoir for HIV-1. This reservoir is activated within DCs by CD40L and upon interaction with T cells, and the virus then spreads rapidly to other T cells.

Anti-HIV Agents↗
PubMed1991

Inhibition of duck hepatitis B virus replication in vitro by 2',3'-dideoxy-3'-azidothymidine and related compounds.

We have adopted the in vitro hepatocyte culture system of the duck infected with duck hepatitis B virus (HDBV) to an anti-viral assay system. Using this method, we found that 2',3'-dideoxy-3'-azidothymidine (N3dT) and 2',3'-dideoxy-3'-O-methylthymidine (OMeT) had antiviral effects against DHBV replication in the concentrations of 20-50 mumol/l and 4-40 mumol/l, respectively. The N3dT inhibited the single strand DNA formation (negative strand), which is an intermediate of virus replication. However, the inhibition of single strand DNA synthesis by OMeT was relatively weak. These two compounds may have different mechanisms of DHBV DNA replication inhibition. Two other 3'-substituted pyrimidine analogues tested were very weak inhibitors. Antiviral agents that inhibit the reverse transcriptase activity of the hepadnavirus DNA polymerase could be potential candidates for the chemotherapy of these viruses.

Animals↗
PubMed1990

Inhibition of hepatitis A virus replication in vitro by antiviral compounds.

Forty antiviral compounds were screened for inhibitory effect on hepatitis A virus (HAV) antigen expression in the human hepatoma cell line PLC/PRF/5. Ribavirin, amantadine, glycyrrhizin, and pyrazofurin were selected in this screening test and were studied further. The selectivity indices of these four compounds, calculated as the ratio of 50% cytotoxic dose (determined by the trypan blue exclusion and by inhibition of [3H] leucine incorporation) to the 50% effective dose (determined by the viral antigen expression), were 4.6 and 3.0 with ribavirin, 5.3 and 5.9 with amantadine, 15.2 and 16.9 with glycyrrhizin, and 45.4 and 74.6 with pyrazofurin. All four compounds resulted in concentration-dependent reductions of HAV antigen expression and HAV infectivity. Ribavirin, amantadine, pyrazofurin, and glycyrrhizin emerged, from the present study, as promising candidates for chemotherapy of acute hepatitis A.

Antigens, Viral↗
PubMed1990

Dextran sulfate inhibits the fusion of influenza virus with model membranes, and suppresses influenza virus replication in vivo.

The effect of dextran sulfate and related compounds on the fusion of influenza A virus with model membranes, composed of dioleylphosphatidyl-choline and cholesterol (1:0.5), was investigated by a fusion assay based on de-quenching of fluorescence of octadecyl-rhodamine-HC1 (R18). Dextran sulfate samples of molecular weight of 500,000, 8,000 and 5,000 were found to be potent inhibitors of the virus-liposome fusion process. Polygalacturonic acid also showed anti-fusion activity, but to a lesser extent. Uncharged dextran, positively charged diethylaminoethyldextran, and the monomer glucosamin-1,6-disulfate were ineffective. It was shown that dextran sulfate interacts with the virus. Our results suggest that dextran sulfate binds to and inactivates the viral fusion protein.

Cytopathogenic Effect, Viral↗