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Results for “Virus Replication”

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PubMedDate not supplied

Correlation of hepatocyte HBsAg expression with virus replication and liver pathology.

To elucidate the biologic significance of hepatocyte HBsAg, its expression patterns were correlated with virus replication and liver pathology in 578 liver biopsies taken from chronic HBsAg carriers aged 1 to 80 years. Five major patterns of hepatocyte HBsAg were identified: homogeneous [intense and discrete, (Pattern A), faint and discrete, (Pattern B) and faint and grouped (Pattern C)]; globular or spotty (Pattern D), and marginal (Pattern E). Pattern A was always associated with viremia and also very frequently with membrane HBsAg expression, but rarely with active liver disease. It occurred most commonly in HBeAg-positive carrier children and young adults, reflecting an early immune tolerance phase with active virus replication. Pattern B was also usually associated with viremia, but very commonly associated with active disease (70%), reflecting active virus replication with enhanced immune response. Pattern E (marginal HBsAg), which was always in group distribution resembling a clonal expansion, predominated the HBeAg-negative phase and was associated with absence of viremia and occurred mostly in older adults with inactive bipolar disease spectrum (normal liver/mild disease or cirrhosis/hepatocellular carcinoma); this reflects a late phase of inactive virus replication or integration. Patterns C and D did not correlate well with viremia, but also tended to have inactive diseases as did Pattern E. These findings suggest that hepatocyte HBsAg expression is closely related to the natural course of chronic hepatitis B virus infection.

Adolescent↗

PubMed1995

Inhibition of human immunodeficiency virus replication by nonimmunosuppressive analogs of cyclosporin A.

Analogs of the immunosuppressive cyclic undecapeptide cyclosporin A (CsA) with substitutions in positions 1, 4, 6, and/or 11 were rationally designed to possess substantially diminished or no immunosuppressive activity. When these compounds were assayed for their capacity to interfere with the replication of human immunodeficiency virus, some displayed a potent antiviral activity in newly infected cells. However, only CsA could interfere with virus replication in persistently infected cells. One CsA analog with antiviral activity costimulated the phytohemagglutinin-induced production of interleukin 2 by human lymphocytes. Human immunodeficiency virus particles from drug-exposed cells showed lower infectivity than virions from untreated cells. Thus, these nonimmunosuppressive analogs of CsA constitute a promising class of lead compounds to develop drugs for effective treatment of the acquired immunodeficiency syndrome.

Antiviral Agents↗

PubMed1986

Effect of interferon on herpes simplex virus replication in murine macrophage-like cell lines.

The effect of interferon on the replication of herpes simplex virus types 1 and 2 was studied in two murine macrophage-like cell lines which differ in their ability to synthesize interferon. Higher titers of herpes simplex virus type 1 occurred in PU5-1.8 cell cultures where interferon was not produced than in J774A.1 cell cultures where low amounts of interferon were produced. Herpes simplex virus type 2 replicated poorly in both types of cell cultures. Interferon synthesis was induced in J774A.1 cell cultures but not in PU5-1.8 cell cultures. Exogenously added interferon was shown to inhibit virus replication, however the restrictiveness of these cells to HSV replication was not relieved by treating cell cultures with anti-interferon serum. These results show that factors other than induced interferon regulate the replication of herpes simplex viruses in these cells and suggest that induced interferon synthesis does not affect herpes simplex virus replication in macrophages.

Animals↗

PubMed1994

Heat shock proteins and virus replication: hsp70s as mediators of the antiviral effects of prostaglandins.

Acute infection of mammalian cells with several types of RNA and DNA viruses often results in induction of heat-shock gene expression. The presence of hsp70 in intact virions, as well as the transient association of HSP with viral proteins and assembly intermediates during virus replication, has also been reported in several experimental models. Moreover, a possible role of heat shock proteins in the beneficial effect of fever and local hyperthermia during acute virus infection has been hypothesized. However, the role of HSP in virus replication remains to be defined. At the beginning of the 1980s, the use of virus models to investigate the molecular events that follow the exposure of mammalian cells to prostaglandins led to the serendipitous discovery that specific arachidonic acid derivatives are potent inhibitors of virus replication. This finding was rapidly followed by the observation that treatment of virus-infected cells with the antiviral prostaglandin A1 (PGA1) resulted in the accumulation of a 70 KDa cellular protein, which was identified as hsp70. It is now well established that cyclopentenone prostaglandins, which exert potent antiviral activity in several DNA and RNA virus models, induce hsp70 synthesis through cycloheximide-sensitive activation of heat shock transcription factor. This chapter discusses the role of heat shock proteins in the control of virus replication and summarizes the results of our recent work, which indicate that hsp70 is actively involved in the antiviral activity of prostaglandins.

Animals↗

PubMed1992

Zidovudine inhibits hepatitis B virus replication.

Hepatitis B virus DNA polymerase is a viral enzyme that can use viral DNA as well as viral RNA as a template for DNA synthesis. Since both activities are essential for the production of new virus particles, blocking of this enzyme should reduce viral replication. In the present study the in vitro effect of zidovudine triphosphate on hepatitis B virus DNA polymerase activity and the in vivo effect of zidovudine on viral replication in chronic HBsAg-positive patients are investigated. Zidovudine triphosphate inhibited in vitro DNA polymerase activity by 50% at a concentration of 0.3 microM. Serum DNA polymerase activity was significantly reduced in 7 patients who received zidovudine (200 mg orally 4 times daily) for one week. A dose-response effect was suggested by the results found for 6 patients who received 100 mg, 200 mg and 300 mg orally 4 times daily for one week with 2 drug-free weeks between each course. We conclude that zidovudine may be of value for non-responders to alpha-interferon therapy or patients with high initial levels of viral replication prior to the start of interferon treatment.

Administration, Oral↗

PubMed1999

Hepatitis B virus replication: novel roles for virus-host interactions.

Chronic hepatitis B continues to be one of the most widespread and serious viral infections in humans worldwide. Several fundamental aspects of the molecular biology of its causative agent, hepatitis B virus, are meanwhile understood in some detail. However, recent research has emphasized that the dependence of the viral infectious cycle on cellular factors is far greater than previously anticipated. More and more intracellular interactions between viral and cellular components are discovered, and probably each individual step of genome replication will turn out to involve several host factors. Prominent examples are the activation of the viral reverse transcriptase, P protein, by chaperones, and the nucleocytoplasmic trafficking of viral nucleic acids by as yet unidentified components of the host machinery. Some of these new developments will be described here but many more can be expected to follow. Identifying these host factors and characterizing their interactions with the viral components will certainly reveal novel targets for specific antiviral strategies.

Hepatitis B Virus, Duck↗

PubMed1990

Identification of foot-and-mouth disease virus replication in vaccinated cattle by antibodies to non-structural virus proteins.

Antibodies raised in cattle against foot-and-mouth disease virus by vaccination or by experimental infection were distinguished. Vaccination elicited only antibodies to virus capsid proteins and the polymerase 3D. Virus replication in cattle elicited additional antibodies directed against the non-structural proteins 2B, 2C, 3AB1, and/or 3C irrespective of prior vaccination or whether the cattle exhibited symptoms of disease. Non-permissive mice inoculated with virus responded in the same way, indicating that antibodies raised due to the transient presence of antigen are safely recognized by the method applied which was radioimmunoprecipitation. All kinds of infections were thus detected and it was possible to differentiate between cattle exposed or not exposed to challenge in the field, and further between protected animals and possible virus carriers.

Animals↗

PubMed2006

Evaluation of synthetic oligonucleotides as inhibitors of West Nile virus replication.

A series of synthetic oligonucleotide phosphorothioate 15-mers were generated against specific sequences in the West Nile virus RNA genome. These antisense oligonucleotides targeted (1) conserved features of the West Nile virus RNA genome that may be expected to lead to inhibition of virus replication since such features play essential roles in the virus lifecycle; (2) G-quartet oligonucleotides with potential facilitated uptake properties and that also targeted conserved sequences among a range of West Nile virus strains. Several formulations with significant in vitro antiviral activity were found. Among the active oligonucleotides were examples that targeted both C-rich RNA sequences of the West Nile RNA genome as well as recognized conserved sequences key to West Nile virus replication. Since the antiviral activity of the latter oligonucleotides diminished upon 2'-O-methyl substitution, it is likely that their activity involves RNase H-catalyzed RNA degradation. One G-rich oligonucleotide that did not target a West Nile virus RNA sequence also was found. These results suggest the potential of antisense strategies for the control of West Nile virus replication if the attendant problem of oligonucleotide delivery can be adequately addressed.

Animals↗

PubMed2001

Cucurbit protoplast isolation for the study of plant virus replication.

A cucurbit protoplast isolation protocol was established for the study of plant virus replication in vivo. This protocol is applicable to both cucumber and squash leaf tissue with significant increases in yields of viable protoplasts suitable for electroporation, compared to other published methods. A combination of Cellulase RS, Macerozyme R10 and mannitol was used as digestion enzymes and osmoticum. An average of 1.7x10(7) protoplasts per gram of fresh leaf tissue were obtained from cucumber cultivar Bet-alpha. Both cucumber cultivar Shimson and squash cultivar First Taste produced an average yield of 6.0x10(6) protoplasts per g of fresh leaf tissue. Electroporation of 10 microg of Zucchini yellow mosaic potyvirus (ZYMV-S) RNA into the protoplasts resulted in virus replication and synthesis of coat protein (CP). SDS-PAGE and immunoblotting were used to detect the CP 48 h post-electroporation. This protocol is highly reproducible and will assist researchers who require cucurbit protoplasts to study virus replication.

Cell Separation↗

PubMed1990

Variable expression of preS1 antigen in serum during chronic hepatitis B virus infection: an accurate marker for the level of hepatitis B virus replication.

The expression of the preS1 antigen of hepatitis B virus in sera from chronic HBsAg carriers was studied using a specific monoclonal antibody F35.25 in an original, double-immunoradiometric assay. The antibody F35.25 recognized an epitope located between amino-acid residues 32 and 53 on the preS1 sequence of the large HBsAg protein. This domain could be involved in the recognition of hepatitis B virus by hepatocyte receptors. PreS1 antigen detection by monoclonal antibody F35.25 closely correlated with the presence of complete virions in the serum of HBsAg carriers, as demonstrated by ultracentrifugation-gradient experiments and electron-microscopical examination. Of the 19 HBsAg carriers with chronic liver disease, preS1 antigen was detected in 17 (90%): all of the 11 HBeAg- and hepatitis B virus-DNA--positive cases (group 1) and six of eight anti-HBe--positive cases with low levels of hepatitis B virus replication (group 2). PreS1 antigen/HBsAg ratios parallel to preS1 antigen titers were significantly higher in the HBeAg-positive group (34% and 1:10(6] than in the anti-HBe--positive group (18% and 1:10(2]. In contrast, preS1 antigen was not detected in 18 (90%) of the 20 HBsAg healthy carriers positive for anti-HBe and negative for serum hepatitis B virus-DNA (group 3). Our results show that in chronic HBsAg carriers the serum expression of preS1 antigen correlates well with the level of hepatitis B virus replication (serum hepatitis B virus-DNA and/or liver HBcAg) and that it may be useful in assessing the clinical importance of the chronic viral infection.

Biomarkers↗

PubMed1997

Development of a novel anti-HIV-1 agent from within: effect of chimeric Vpr-containing protease cleavage site residues on virus replication.

Effective antiviral agents will be of great value in controlling virus replication and delaying the onset of HIV-1-related disease symptoms. Current therapy involves the use of antiviral agents that target the enzymatic functions of the virus, resulting in the emergence of resistant viruses to these agents, thus lowering their effectiveness. To overcome this problem, we have considered the idea of developing novel agents from within HIV-1 as inhibitors of virus replication. The specificity of the Vpr protein for the HIV-1 virus particle makes it an attractive molecule for the development of antiviral agents targeting the events associated with virus maturation. We have generated chimeric Vpr proteins containing HIV-1-specific sequences added to the C terminus of Vpr. These sequences correspond to nine cleavage sites of the Gag and Gag-Pol precursors of HIV-1. The chimeric Vpr constructs were introduced into HIV-1 proviral DNA to assess their effect on virus infectivity using single- and multiple-round replication assays. The virus particles generated exhibited a variable replication pattern depending on the protease cleavage site used as a fusion partner. Interestingly, the chimeric Vpr containing the cleavage sequences from the junction of p24 and p2, 24/2, completely abolished virus infectivity. These results show that chimeric proteins generated from within HIV-1 have the ability to suppress HIV-1 replication and make ideal agents for gene therapy or intracellular immunization to treat HIV-1 infection.

Anti-HIV Agents↗

PubMed1993

Inhibition of visna virus replication by 2',3'-dideoxynucleosides and acyclic nucleoside phosphonate analogs.

A series of acyclic nucleoside phosphonate (ANP) and 2',3'-dideoxynucleoside (ddN) derivatives were evaluated for their inhibitory effects on visna virus replication and maedi/visna virus-induced syncytium formation in sheep choroid plexus cells. Most ANP derivatives inhibited virus replication and syncytium formation within a concentration range of 0.2 to 1.8 microM. Among the most active ANP derivatives ranked (R)-9-(2-phosphonomethoxypropyl)adenine, (R)-9-(2-phosphonomethoxypropyl)-2,6-diaminopurine, and (S)-9-(3-fluoro-2-phosphonomethoxypropyl)adenine. Of the ddN derivatives, 2',3'-dideoxycytidine (ddCyd) proved to be the most inhibitory to visna virus-induced syncytium formation (50% effective concentration, 0.02 microM). The purine ddN analogs (i.e., 2',3'-dideoxyinosine, 2',3'-dideoxyadenosine, 2',3'-dideoxyguanosine, and 2,6-diaminopurine-2',3'-dideoxyribosine) were 10- to 30-fold less effective, and the thymidine derivatives 2',3'-didehydro-2',3'-dideoxythymidine (D4T) and 3'-azido-2',3'-dideoxythymidine (AZT) were more than 500-fold less inhibitory to visna virus than ddCyd. The 5'-triphosphate forms of AZT and D4T were 100- to 600-fold more inhibitory to visna virus particle-derived reverse transcriptase than was the 5'-triphosphate of ddCyd. The apparent discrepancy between the inhibitory effects of these ddN derivatives on virus replication and viral reverse transcriptase activity most likely reflects differences in the metabolic conversion of ddCyd versus D4T and AZT in sheep choroid plexus cells.

Animals↗

PubMed2005

Mutations within the nuclear localization signal of the porcine reproductive and respiratory syndrome virus nucleocapsid protein attenuate virus replication.

Porcine reproductive and respiratory syndrome virus (PRRSV) is an RNA virus replicating in the cytoplasm, but the nucleocapsid (N) protein is specifically localized to the nucleus and nucleolus in virus-infected cells. A 'pat7' motif of 41-PGKK(N/S)KK has previously been identified in the N protein as the functional nuclear localization signal (NLS); however, the biological consequences of N protein nuclear localization are unknown. In the present study, the role of N protein nuclear localization during infection was investigated in pigs using an NLS-null mutant virus. When two lysines at 43 and 44 at the NLS locus were substituted to glycines, the modified NLS with 41-PGGGNKK restricted the N protein to the cytoplasm. This NLS-null mutation was introduced into a full-length infectious cDNA clone of PRRSV. Upon transfection of cells, the NLS-null full-length clone induced cytopathic effects and produced infectious progeny. The NLS-null virus grew to a titer 100-fold lower than that of wild-type virus. To examine the response to NLS-null PRRSV in the natural host, three groups of pigs, consisting of seven animals per group, were intranasally inoculated with wild-type, placebo, or NLS-null virus, and the animals were maintained for 4 weeks. The NLS-null-infected pigs had a significantly shorter mean duration of viremia than wild-type-infected pigs but developed significantly higher titers of neutralizing antibodies. Mutations occurred at the NLS locus in one pig during viremia, and four types of mutations were identified: 41-PGRGNKK, 41-PGGRNKK, and 41-PGRRNKK, and 41-PGKKSKK. Both wild-type and NLS-null viruses persisted in the tonsils for at least 4 weeks, and the NLS-null virus persisting in the tonsils was found to be mutated to either 41-PGRGNKK or 41-PGGRNKK in all pigs. No other mutation was found in the N gene. All types of reversions which occurred during viremia and persistence were able to translocate the mutated N proteins to the nucleus, indicating a strong selection pressure for reversion at the NLS locus of the N protein in vivo. Reversions from NLS-null to functional NLS in the tonsils suggest a possible correlation of viral persistence with N protein nuclear localization. These results show that N protein nuclear localization is non-essential for PRRSV multiplication but may play an important role in viral attenuation and in pathogenesis in vivo.

Amino Acid Sequence↗

PubMed2002

Hepatitis C virus RNA quantitation in hepatic veins and peripheral blood in patients with liver cirrhosis: evidence for low level intrahepatic hepatitis C virus replication in advanced liver disease.

BACKGROUND: Very few data exist concerning the level of hepatitis C virus replication within the cirrhotic liver and its relationship to disease severity and progression. AIMS: To quantitate hepatitis C virus RNA in hepatic vein blood and peripheral blood in patients with cirrhosis, to evaluate the correlation of hepatitis C virus levels in paired blood samples, and to compare the results with clinical features. PATIENTS: A series of 25 patients with hepatitis C virus-related liver cirrhosis undergoing hepatic vein catheterization were studied: 11 belonged to Child Pugh class A, 8 to class B and 6 to class C. RESULTS: Hepatitis C virus RNA levels did not differ between hepatic vein blood and peripheral blood (p = 0.26), despite a trend towards higher peripheral hepatitis C virus RNA levels. Hepatitis C virus RNA levels did not differ between patients with genotype 1b and non-1b either in hepatic veins or peripheral blood. Hepatitis C virus loads varied according to the severity of cirrhosis. The patients with more severe liver disease had significantly lower RNA titres than those with less advanced cirrhosis, both in hepatic veins (p = 0.002) and peripheral blood (p = 0.004). No differences in hepatitis C virus load were observed between patients in Child Pugh classes B and C. CONCLUSIONS: The present data show that in patients with cirrhosis hepatitis C virus RNA concentrations do not differ between hepatic blood and peripheral blood and, furthermore, confirm that hepatitis C virus replication is reduced in patients with advanced cirrhosis, compared with patients with less severe liver disease. These findings might indicate that patients with liver cirrhosis maintain an efficient intrahepatic hepatitis C virus replication even in end-stage disease, although hepatitis C virus viraemia decreases according to the severity of liver disease.

Aged↗

PubMed2005

Cooperative effect of gag proteins p12 and capsid during early events of murine leukemia virus replication.

The Gag polyprotein of murine leukemia virus (MLV) is processed into matrix (MA), p12, capsid (CA), and nucleocapsid (NC) proteins. p12 affects early events of virus replication and contains a PPPY motif important for virus release. To probe the functions of p12 in the early steps of MLV replication, we tested whether p12 can be replaced by spleen necrosis virus (SNV) p18, human immunodeficiency virus type 1 p6, or Rous sarcoma virus p2b. Analyses revealed that all chimeras generated virions at levels similar to that of MLV gag-pol; however, none of them could support MLV vector replication, and all of them exhibited severely reduced DNA synthesis upon virus infection. Because a previously reported SNV gag-MLV pol chimera, but not the MLV hybrid with SNV p18, can support replication of an MLV vector, we hypothesized that other Gag proteins act cooperatively with p12 during the early phase of virus replication. To test this hypothesis, we generated three more MLV-based chimeras containing SNV CA, p18-CA, or p18-CA-NC. We found that the MLV chimera containing SNV p18-CA or p18-CA-NC could support MLV vector replication, but the chimera containing SNV CA could not. Furthermore, viruses derived from the MLV chimera with SNV CA could synthesize viral DNA upon infection but were blocked at a post-reverse-transcription step and generated very little two long terminal repeat circle DNA, thereby producing a phenotype similar to that of the provirus formation-defective p12 mutants. Taken together, our data indicate that when p12/p18 or CA was from different viruses, despite abundant virus production and proper Gag processing, the resulting viruses were not infectious. However, when p12/p18 and CA were from the same virus, even though they were from SNV and not MLV, the resulting viruses were infectious. Therefore, these results suggest a cooperative effect of p12 and CA during the early events of MLV replication.

Capsid Proteins↗

PubMed1984

Verapamil inhibits influenza A virus replication.

Calcium channel blockers reduce Ca++ flux through membrane channels and may inhibit intracellular Ca++-dependent synthetic and regulatory activities by binding to calmodulin. We have found that Verapamil, a calcium channel blocker, inhibits influenza virus replication in Madin-Darby canine kidney cells and in murine pulmonary macrophages and that this antiviral effect occurs with drug addition late in the replication cycle. Chlorpromazine, a drug which binds to calmodulin, also inhibited influenza virus replication in these tissue culture systems. We suggest that Verapamil and chlorpromazine inhibit influenza virus replication by interfering with calmodulin-dependent intracellular activities necessary for late synthetic steps or virus assembly steps and that calcium channel blockers provide a new probe for investigating influenza virus replication.

Animals↗

PubMed1971

Aspects of influenza C virus replication.

Influenza C virus antigen could be detected by immunofluorescence in chick amniotic epithelium 4 hr. after inoculation with undiluted amniotic fluid. Antigen could be detected in the nucleus of rhesus monkey kidney tissue cultures 10 hr. after infection. Only cytoplasmic fluorescence was observed 17-21 hr. after infection.The pattern of replication was similar to that reported for group I myxoviruses, indicating that the virus is correctly classified as an influenza virus.

Amnion↗

PubMed2006

Aggresomes and autophagy generate sites for virus replication.

The replication of many viruses is associated with specific intracellular compartments called virus factories or virioplasm. These are thought to provide a physical scaffold to concentrate viral components and thereby increase the efficiency of replication. The formation of virus replication sites often results in rearrangement of cellular membranes and reorganization of the cytoskeleton. Similar rearrangements are seen in cells in response to protein aggregation, where aggresomes and autophagosomes are produced to facilitate protein degradation. Here I review the evidence that some viruses induce aggresomes and autophagosomes to generate sites of replication.

Autophagy↗