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Results for “VIRAL INTERFERENCE”

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PubMed1989

Approaches to antiviral chemotherapy.

Most of the drugs used today in the treatment of viral infections in man are purine-pyrimidine antimetabolites that interfere with viral replication. Work at Southern Research Institute has identified a number of compounds of this type with promising antiviral activity in both cell culture and rodent test systems. By far the most active and selective agents are carbocyclic nucleoside analogs in which the oxygen of the furanose ring is replaced by a methylene group. The effects of this change on the metabolism and antiviral activity of these compounds is discussed below.

Animals↗
PubMed2005

Interferon and the central nervous system.

Interferons (IFNs) were discovered as natural antiviral substances produced during viral infection and were initially characterized for their ability to "interfere" with viral replication, slow cell proliferation, and profound alteration of immunity. The IFNs are synthesized and secreted by monocytes, macrophages, T-lymphocytes, neurons, and glia cells. The different IFNs are classified into three classes: alpha, beta, and gamma. alpha-IFN produced in the brain exerts direct effects on the brain and endocrine system by activating the neurosecretory hypothalamic neurons and regulates the hypothalamic-pituitary-adrenocortical axis. IFNs modulate neurophysiological activities of many brain region involving in pain, temperature, and food intake regulation. alpha-IFN administration activates the sympathetic nerves innervating components of the immune system. IFNs may serve as regulatory mediators between the central nervous system, the immune system, and endocrine system. IFN is used as immunologic therapy to treat various hematologic malignancies and infectious ailments and autoimmune diseases.

Animals↗
PubMed2006

Small molecule and biologic inhibitors of hepatitis C virus: a symbiotic approach.

Chronic infection with hepatitis C virus (HCV) remains a global health concern. Using both in vitro and cell-based assays, a series of small molecule agents specific for the viral RNA-dependent RNA polymerase have been shown to interfere with viral RNA replication. Although no agents targeting this viral enzyme have demonstrated sustained efficacy in infected patients as measured by reduction in viral load at 72 weeks post-treatment, proof-of-concept has been achieved in the clinic. A comprehensive account of the structure-activity relationship for nucleoside and non-nucleoside inhibitors of HCV polymerase, as well as consideration of early discovery biologic approaches targeting NS5B are reviewed.

Animals↗
PubMed1999

The application of ribozymes to HIV infection.

During the past decade major advances have been made in combating HIV infection and reducing the incidence of AIDS in the western world. Despite optimism about such progress, there is accumulating evidence to suggest that new forms of therapy may be necessary to combat viral resistance to current drugs as well as to provide alternatives to life-long drug use. Genetic forms of therapy are considered to be an important alternative to current drug therapy. One therapeutic agent that can be tailored to inhibit viral infection is catalytic RNA or ribozymes. These RNAs can be engineered to site-specifically cleave targeted RNAs, thereby minimizing cellular toxicity associated with conventional drugs. A potential advantage of ribozymes over other forms of genetic therapy aside from target specificity is their potential for interfering with different stages of the viral life cycle. Ribozymes can be designed and expressed to interfere with viral entry, messenger RNA function and viral packaging. For the two simplest ribozyme motifs, the hammerhead and hairpin, there are hundreds of potential sites along the viral genome. Combinatorial use of ribozymes allows multiple HIV-1 sequences to be attacked simultaneously, thereby circumventing viral resistance through mutation. Ribozymes can also be designed to inhibit expression of cellular targets, which are required for HIV-1 infection. The successful applications of ribozymes against HIV-1 in preclinical settings has now set the stage for their testing in patient trials and several first phase clinical trials are currently underway.

Animals↗
PubMed1977

In vivo interference in vesicular stomatitis virus infection.

Inactivated defective interfering and complete particles of vesicular stomatitis virus given intracerebrally to adult mice protect them against challenge with homologous virus whether this is given at the same time or several days later. Two separate protective processes appear to be involved. The first, which comes into operation immediately after inoculation, is also effective against heterologous strains of vesicular stomatitis virus, rabies (another rhabdovirus), and a neurotropic strain of foot-and-mouth disease virus. The second, later effect, which is strain specific, appears to be correlated with the appearance of circulating neutralizing antibody. Our results suggest that the protective effect that Holland and his colleagues described using defective interfering particles of vesicular stomatitis virus may also be accounted for by an immunological mechanism rather than one involving interference.

Animals↗
PubMed1975

Cellular resistance to arbovirus infection.

When an arbovirus enters an arthropod in an infected blood meal, several mechanisms may interact to affect its life cycle and ultimate transmissibility. Intrinsic absolute failure in the establishment of infection must be contrasted with infection that is successfully established but is variably modulated in its viral yield throughout the vector's life-span. Degrees of vertebrate host resistance make this modulation a central factor in determining whether an arthropod is an important vector in nature; moreover, human intervention that affects modulating mechanisms may become a basis for disease control. In the absence of evidence of real immune resistance to arbovirus infections in arthropods, other more primitive modulating mechanisms must be considered: interferonlike substances may be formed in arthropod cells; arthropod cells may "cure" themselves by a unique endophagocytic digestion of their virus burden; homologous interference with viral replicative processes may be mediated via wild or mutant viral RNA species acting to shut down further RNA synthesis; and homologous interference may be mediated by RNA of defective-interfering virus formed earlier in infection.

Aedes↗
PubMedDate not supplied

Hepatitis C: therapeutic perspectives.

Continuous efforts are vital to develop new treatment strategies to improve sustained response rates, especially for difficult to treat patients infected with the hepatitis C virus. Despite the introduction of ribavirin, more than 50% of the patients do not eliminate the virus with the current standard therapy of interferon-a (IFN) and ribavirin. Options to further enhance response rates include modification of the IFN-dosing schedule with daily dosing of IFN, new IFN such as consensus interferon or modified IFN with longer half-life and more favourable pharmacokinetics such as pegylated IFN (PEG-IFN). Clinical trials with new IFN showed that consensus IFN may improve response rates in unsuccessfully pre-treated patients and patients with HCV-genotype-1. Treatments with PEG-IFN will double response rates achieved with standard IFN monotherapy. The combination of PEG-IFN and ribavirin improves the virological response to more than 50% and even to more than 80% in patients with genotype 2 or 3. By now, standard therapy of chronic hepatitis C has been changed to the combination of PEG-IFN plus ribavirin. Future anti-viral drugs may comprise molecules that directly inhibit HCV proteins and interfere with viral replication. NS3/4A serine protease, ribonucleic acid (RNA) helicase, RNA-dependent RNA polymerase may be potential targets for new drugs. Furthermore antisense oligonucleotides or ribozymes may become new treatment options to inhibit HCV replication. Finally, immunotherapies to enhance HCV-specific immune responses are also attractive strategies to control HCV infection and to prevent chronic liver disease.

Antiviral Agents↗
PubMed2003

P1/HC-Pro, a viral suppressor of RNA silencing, interferes with Arabidopsis development and miRNA unction.

The molecular basis for virus-induced disease in plants has been a long-standing mystery. Infection of Arabidopsis by Turnip mosaic virus (TuMV) induces a number of developmental defects in vegetative and reproductive organs. We found that these defects, many of which resemble those in miRNA-deficient dicer-like1 (dcl1) mutants, were due to the TuMV-encoded RNA-silencing suppressor, P1/HC-Pro. Suppression of RNA silencing is a counterdefensive mechanism that enables systemic infection by TuMV. The suppressor interfered with the activity of miR171 (also known as miRNA39), which directs cleavage of several mRNAs coding for Scarecrow-like transcription factors, by inhibiting miR171-guided nucleolytic function. Out of ten other mRNAs that were validated as miRNA-guided cleavage targets, eight accumulated to elevated levels in the presence of P1/HC-Pro. The basis for TuMV- and other virus-induced disease in plants may be explained, at least partly, by interference with miRNA-controlled developmental pathways that share components with the antiviral RNA-silencing pathway.

Arabidopsis↗
PubMed1981

Neutralization of vesicular stomatitis virus (VSV) by human complement requires a natural IgM antibody present in human serum.

Neutralization of VSV by human serum ws previously shown to involve C1, C2, C3, and C4 of the classical complement (C) pathway. All normal human sera tested were equivalently active in this regard. However, purified C1, C2, C3, and C4 were unable to mediate VSV neutralization. In the present studies an additional factor required for C-mediated neutralization was isolated from normal human serum and identified as a natural IgM antibody specific for a viral encoded antigen. Purified IgM bound to the virus and formed a complex that activated component C1. Normal serum concentrations of purified IgM, C1, C2, C3, C4 neutralized VSV to the same extent as normal serum. Purified IgM did not neutralize VSV alone or in conjunction with C1, C2, and C4. Inclusion of C3 resulted in full neutralization and C3b binding to the virus was demonstrated. Thus, normal human serum contains a natural antibody of the IgM class that is directed toward a viral antigen. The antibody facilitates neutralization by forming an immune complex that activates C1 and thus efficiently initiates the classical pathway at the viral surface. Neutralization occurs with C3b deposition on the viral envelope and probably results from a blanket of C protein that interferes with viral attachment to susceptible cells.

Absorption↗
PubMed2000

Identification and characterization of a shared TNFR-related receptor for subgroup B, D, and E avian leukosis viruses reveal cysteine residues required specifically for subgroup E viral entry.

Genetic and receptor interference data have indicated the presence of one or more cellular receptors for subgroup B, D, and E avian leukosis viruses (ALV) encoded by the s1 allele of the chicken tvb locus. Despite the prediction that these viruses use the same receptor, they exhibit a nonreciprocal receptor interference pattern: ALV-B and ALV-D can interfere with infection by all three viral subgroups, but ALV-E only interferes with infection by subgroup E viruses. We identified a tvb(s1) cDNA clone which encodes a tumor necrosis factor receptor-related receptor for ALV-B, -D, and -E. The nonreciprocal receptor interference pattern was reconstituted in transfected human 293 cells by coexpressing the cloned receptor with the envelope (Env) proteins of either ALV-B or ALV-E. This pattern of interference was also observed when soluble ALV surface (SU)-immunoglobulin fusion proteins were bound to this cellular receptor before viral challenge. These data demonstrate that viral Env-receptor interactions can account for the nonreciprocal interference between ALV subgroups B, D, and E. Furthermore, they indicate that a single chicken gene located at tvb(s1) encodes receptors for these three viral subgroups. The TVB(S1) protein differs exclusively at residue 62 from the published subgroup B- and D-specific receptor, encoded by the s3 allele of tvb. Residue 62 is a cysteine in TVB(S1) but is a serine in TVB(S3), giving TVB(S1) an even number of cysteines in the extracellular domain. We present evidence for a disulfide bond requirement in TVB(S1) for ALV-E infection but not for ALV-B infection. Thus, ALV-B and ALV-E interact in fundamentally different ways with this shared receptor, a finding that may account for the observed biological differences between these two ALV subgroups.

Amino Acid Sequence↗
PubMed2006

Betanodavirus B2 is an RNA interference antagonist that facilitates intracellular viral RNA accumulation.

Betanodaviruses are small positive-sense bipartite RNA viruses that infect a wide variety of fish species and are notorious for causing lethal outbreaks in juvenile fish hatcheries worldwide. The function of a small nonstructural protein, B2, encoded by the subgenomic RNA3 of betanodaviruses, has remained obscure. Greasy grouper nervous necrosis virus, a betanodavirus model, was used to develop a facile DNA-based reverse genetics system that recapitulated the virus infection cycle, and we used this system to show that B2 is a small nonstructural protein that is essential for high level accumulation of viral RNA1 after RNA transfection of fish, mammalian, and avian cells. The defect in RNA1 accumulation in a B2 mutant was partially complemented by supplying B2 RNA in trans. Confocal analysis of the cellular distribution of B2 indicated that B2 is able to enter the nucleus and accumulates there during the late stages of GGNNV infection. Using human HeLa cells as a cellular RNA interference model, we found that B2 could efficiently antagonize RNA interference, which is a property shared by the distantly related alphanodavirus B2 proteins. This function provides appears to provide an explanation, at least in part, for why B2 mutant RNA1 is severely impaired in its intracellular accumulation.

HeLa Cells↗
PubMed1981

Intrinsic interference between swine influenza and fowl plague virus.

Multiplication of swine influenza (SW) virus is inhibited by fowl plaque virus (FPV) at the level of RNA synthesis when host cells are infected with both viruses at a high multiplicity of infection. Under these conditions reassortment between the two viruses cannot be detected. The inhibitory effect of FPV is highly reduced and recombinants between the two viruses could be obtained when the cells were superinfected with FPV 1--2 hours after infection with SW virus, or after simultaneous infection with a low multiplicity of infection. The phenomenon is compatible with the intrinsic interference.

Animals↗