Chromosome 21 and the cell growth inhibitory effect of human interferon preparations.
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Alleles↗
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Results for “VIRAL INTERFERENCE”
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Defective interfering particles with covalently linked [+/-]RNA induce interferon.
Defective interfering (DI) particles of vesicular stomatitis virus which contain covalently linked complementary [+]message and [-]anti-message RNA as a single-stranded ribonucleoprotein complex within the particle, are extremely efficient inducers of interferon. A single particle can induce a quantum yield of interferon. A single molecule of double-stranded RNA presumed to form, at least in part, on entry into the cell is thought to induce interferon synthesis. Conventional [-]RNA DI particles with the same polypeptide composition as [+/-]RNA DI particles fail to induce interferon.
Antibodies, Viral↗
Interferon-induced transfer of viral resistance between animal cells.
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Animals↗
Viral pathogenesis and resistance to defective interfering particles.
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Animals↗
Immune and virus-induced interferons may activate cells by different derepressional mechanisms.
Virus-induced interferon (VIF), and immune interferon (IIF) produced by lymphocytes following activation by various mitogens (phytohaemagglutinin, concanavalin A, staphlococcal enterotoxin A) or by specific antigenic stimulation (tuberculin, bacterial toxoids, and viral antigens) show important functional differences. These include different antitumour and immunoregulatory activities and differential inhibition of activity by mercaptoethanol. Another important difference has recently been shown: cells treated with IIF acquire the antiviral state much more slowly than those treated with VIF. This may be due to (1) difference in cellular receptors, (2) presence of an inhibitor of antiviral activity in the IIF preparations, or (3) a different mechanism of activation of the antiviral state by the two types of interferon. The first two hypotheses seem unlikely, since (1) no difference between cell association by the two types of interferon has been detected, and (2) the presence of the slow acting IIF preparation did not inhibit the rapid activation by VIF. The present study shows that the different kinetics of induction of the antiviral state result from a major difference in the mechanism by which IIF and VIF activate cells.
Animals↗
Common pathways of interferon and hormonal action.
The action of interferon as well as polypeptide hormones has been shown to be transmissible between cells, possibly through gap-junctional transfer of secondary messenger molecules. This and other similarities between interferon and polypeptide hormones have led us to propose that there is a common cellular pathway of interferon and hormonal action. If correct, this hypothesis would predict that interferon should cause a species-specific hormonal response and a hormone should induce tissue-specific antiviral activity. If these two responses are mediated by similar secondary messengers, they should be transmissible and cross-activate cells. Here, we show that interferon caused a species-specific hormonal response (noradrenaline-like stimulation of the beat frequency of cultured mouse myocardial cells). Noradrenaline induced an interferon-like antiviral state in mouse myocardial cells but not human amnion (WISH) cells. In conditions which demonstrate interferon-induced transfer of viral resistance, exposure of co-cultures of mouse myocardial cells and WISH cells to either human interferon or noradrenaline caused an increased beat frequency in the myocardial cells and development of antiviral activity in WISH cells, respectively. These studies strongly suggest common pathways of interferon and hormonal stimulation that are transmissible between cells.
Animals↗
Different antiviral spectra of human macrophage interferon activities.
The antiviral activity of alpha-interferon (IFN-alpha) produced by human leukocytes in response to viral infection has been considered to be independent of the virus which induced its production. Recently, however, IFN-alpha has been found to include at least eight different subtypes, as indicated by measurement of antigenic variability, DNA hybridization and amino acid sequencing. We considered the possibility that interferon heterogeneity may play a part in enhancing host antiviral defence and now present data suggesting that purified human macrophages, when exposed to different viruses, produce interferons having differing spectra of antiviral activity. These findings may provide a functional correlation for IFN-alpha heterogeneity.
Humans↗
The isolation of bovine ephemeral fever virus in cell cultures and evidence for autointerference.
Bovine ephemeral fever (BEF) virus was isolated from infected fresh cattle blood directly into Vero cell cultures. One cycle of rapid freeze-thaw destroyed the infectivity of the virus to Vero cells. The infectivity to baby mice by intracerebral inoculation, on the other hand, was only reduced. The occurrence of autointerference due to the presence of defective interfering particles in cell culture was also noted. BEF virus strain 919 was propagated to some extent in bovine kidney, testis and synovial cell monolayers, producing cytopathic effect (CPE) in 24 h. However, the CPE was nonprogressive and the addition of antinomycin D to the medium improved the virus titre only slightly.
Animals↗
Engineering resistance to mixed virus infection in a commercial potato cultivar: resistance to potato virus X and potato virus Y in transgenic Russet Burbank.
Potato virus X (PVX) and potato virus Y (PVY) infection in potato may result in the loss of certification of seed potatoes and affect quality and yield of potatoes in commercial production. We transformed a major commercial cultivar of potato, Russet Burbank, with the coat protein genes of PVX and PVY. Transgenic plants that expressed both CP genes were resistant to infection by PVX and PVY by mechanical inoculation. One line was also resistant when PVY was inoculated with viruliferous green peach aphids. These experiments demonstrate that CP protection is effective against mixed infection by two different viruses and against mechanical and aphid transmission of PVY.
Amino Acid Sequence↗
Long-term protection against SIV-induced disease in macaques vaccinated with a live attenuated HIV-2 vaccine.
The aim of this study was to test the ability of a live attenuated human immunodeficiency virus type 2 (HIV-2) vaccine to protect cynomolgus monkeys against superinfection with a pathogenic simian immunodeficiency virus (SIVsm). This report is an update on our previously reported observation period of nine months. The new data here show that three of four monkeys vaccinated with live HIV-2 were protected against immunosuppression and SIV-induced disease during more than five years of follow-up. The quality of the immunity was permissive for infection, but monkeys that survived showed restricted viral replication in peripheral blood and lymph nodes. This study shows that it is possible to induce protection against a pathogenic heterologous primate lentivirus and to prevent disease in vaccinated monkeys even if infection is not prevented. These findings provide evidence that protection against AIDS can be achieved by immunization.
AIDS Vaccines↗
E1A-induced apoptosis does not prevent replication of adenoviruses with deletion of E1b in majority of infected cancer cells.
Apoptotic pathways are initiated as a cellular defense mechanism to eliminate adenovirus-infected cells. We have investigated how E1A-induced apoptosis interferes with viral replication in cancer cells. We found that E1B19K alone can efficiently suppress E1A-induced apoptosis in cancer cells. Viruses deleted for both E1B19K and E1B55K resulted in cellular DNA degradation. However, less than 20% of human lung cancer cells infected with a virus deleted for both E1B19K and E1B55 K had evidence of chromatin condensation and multiple-micronuclei formation (apoptotic hallmarks); these cells could not produce infectious viral particles. The majority of cancer cells infected with viruses deleted for the entire E1b gene did not undergo extended apoptosis and produced abundant viral progeny. Thus, only a fraction of cancer cells underwent apoptosis and did not allow E1b-deleted viruses to replicate, while the majority of cancer cells were resistant to E1A-induced apoptosis and could support virus-selective replication. The results of this study imply that, in addition to inhibiting E1A-induced apoptosis, E1B proteins may contribute other important roles in the viral life cycle. Our results also suggest that combining virus-induced apoptosis and selective viral replication into one vector will be a novel approach to destroy cancer cells.
Adenoviridae Infections↗
Aberrant, noninfectious HIV-1 particles are released by chronically infected human T cells transduced with a retroviral vector expressing an interfering HIV-1 variant.
The expression of the nonproducer F12-HIV-1 genome has been previously shown to protect the host cell from HIV superinfection. In order to estimate the efficacy of the F12-HIV genome as an anti-HIV reagent also in cells already infected, an HIV-1 chronically infected Hut-78 cell clone (D10) was superinfected with an amphotropic mouse/human pseudotype retrovirus whose genome expresses both the F12-HIV genome and the selection marker gene (i.e. the c-DNA of a truncated form of the nerve growth factor receptor, NGFr) under the control of F12-HIV 5'LTR. D10 cells homogenously expressing the F12-HIV genome (T-D10) released unaltered amounts of retrovirions whose infectivity was, however, dramatically impaired (from 9 x 10(3) in D10 to < 10(0.5). TCID50/ml in T-D10 supernatants). Electron microscopy showed that the morphology of retrovirions released by T-D10 cells was heavily altered, both in size and shape. Furthermore, no retrotranscription products were detectable in CD4 cells challenged with T-D10 retrovirions. For the first time, the block in the infectivity of HIV released from already infected cells through the expression of an anti-HIV retroviral vector was demonstrated. These data could have important implications both from a perspective of F12-HIV-based anti-HIV gene therapy and, in general, on the role that nonproducer and/or defective HIV could play 'in vivo' in HIV infection and AIDS pathogenesis.
Cell Culture Techniques↗
Investigation of RNA transcripts containing HIV-1 packaging signal sequences as HIV-1 antivirals: generation of cell lines resistant to HIV-1.
Based on the success of RNA decoy approaches using RRE and TAR sequences to inhibit HIV-1 replication, we studied the ability of HIV-1 packaging signal sequences to interfere with viral RNA encapsidation and formation of infectious particles. We made a variety of plasmid constructs in which the sequence context or number of repeats of the viral packaging signal was varied, and investigated the ability of these transcripts to inhibit replication of HIV-1 in stably transfected Jurkat T lymphocytes. We found that certain lines showed strong inhibition of HIV-1 replication, an effect that persisted at high input amounts of virus and significantly delayed viral replication for up to 4 weeks. An investigation of the mechanism of inhibition revealed that in these cell lines the packaging efficiency of the genomic HIV-1 transcript was unaffected. Further studies identified an antiviral effect on both HIV-1 and HIV-2 that did not correlate with decoy expression, and was substantially independent of CD4 expression or cellular proliferative capacity. Study of these resistant cell lines may lead to new insights into mechanisms of inhibition of HIV-1 replication.
CD4 Antigens↗
Distinct nuclear body components, PML and SMRT, regulate the trans-acting function of HTLV-1 Tax oncoprotein.
Several viruses target cellular promyelocytic leukemia (PML)-nuclear bodies (PML-NBs) to induce their disruption, marked morphological changes in these structures or the relocation to PML-NB components to the cytoplasm of infected cells. PML conversely interferes with viral replication. We demonstrate that PML acts as a coactivator for the human T-cell leukemia virus type 1 (HTLV-1) Tax oncoprotein without direct binding. Tax was identified within interchromatin granule clusters (IGCs)/RNA splicing bodies (SBs), not PML-NBs; Tax expression did not affect PML-NB formation. Moreover, PML and CBP/p300 cooperatively activated Tax-mediated HTLV-1-LTR-dependent gene expression. Interestingly, two PML mutants, PML-RAR and PMLDelta216-331, which fail to form PML-NBs, could also coactivate Tax-mediated trans-acting function but had no effect on retinoic acid receptor (RAR)- or p53-dependent gene expression. In contrast, SMRT (silencing mediator for retinoic acid and thyroid hormone receptors), a nuclear corepressor found within the matrix-associated deacetylase (MAD) nuclear body, relocalized into Tax-associated nuclear bodies upon coexpression with Tax. SMRT coactivated the trans-acting function of Tax through direct binding. Coexpression of SMRT and PML resulted in an additive activation of Tax trans-acting function. Thus, crosstalk between distinct nuclear bodies may control Tax function.
Base Sequence↗
Structure and properties of human interferon-alpha from Namalwa lymphoblastoid cells.
The chromatographic properties of human interferon-alpha from Namalwa lymphoblastoid cells on Sephadex G-75 are described. The interferons are separated into two groups of four, with apparent molecular weights 19050 and 22000. Some of the latter form dimers at high concentrations. Fractions containing interferon were studied by polyacrylamide-gel electrophoresis in the presence of sodium dodecyl sulphate. Seven of the components had apparent molecular weights in this system, after reduction, of between 18400 and 20900: one component is probably glycosylated and has an apparent molecular weight of 27500. Amino acid sequences of peptides derived from interferon mixtures were determined and are related to published sequences deduced from the nucleotide sequences of cloned complementary DNA coding for interferon-alpha. The results show that the major interferon-alpha species isolated from Namalwa cells do not undergo C-terminal processing. Amino acid analyses of peptides are presented in Supplementary Publication SUP 50117 (28 pages), which has been deposited with the British Library Lending Division, Boston Spa, Wetherby, West Yorkshire LS23 7BQ, U.K., from whom copies can be obtained on the terms indicated in Biochem. J. (1981) 193, 5.
Amino Acid Sequence↗
Regulation of cell proliferation and differentiation by interferons.
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Animals↗
Molecular misreading: the occurrence of frameshift proteins in different diseases.
Neuronal homoeostasis requires a constant balance between biosynthetic and catabolic processes. Eukaryotic cells primarily use two distinct mechanisms for degradation: the proteasome and autophagy of aggregates by the lysosomes. We focused on the UPS (ubiquitin-proteasome system). As a result of molecular misreading, misframed UBB (ubiquitin B) (UBB+1) is generated. UBB+1 accumulates in the neuritic plaques and neurofibrillary tangles in all patients with AD (Alzheimer's disease) and in the neuronal and glial hallmarks of other tauopathies and in polyglutamine diseases such as Huntington's disease. UBB+1 is not present in synucleinopathies such as Parkinson's disease. We showed that UBB+1 causes UPS dysfunction, aggregation and apoptotic cell death. UBB+1 is also present in non-neurological cells, hepatocytes of the diseased liver and in muscles during inclusion body myositis. Other frequently occurring (age-related) diseases such as Type 2 (non-insulin-dependent) diabetes mellitus are currently under investigation. These findings point to the importance of the UPS in diseases and open new avenues for target identification of the main players of the UPS. Treatment of these diseases with tools (e.g. viral RNA interference constructs) to intervene with specific targets is the next step.
Amino Acid Sequence↗
Single nucleotide insertion in the 5'-untranslated region of hepatitis C virus with clearance of the viral RNA in a liver transplant recipient during acute hepatitis B virus superinfection.
Hepatitis C virus (HCV) infection is an important etiology in patients undergoing orthotopic liver transplantation (OLT) world-wide. Antiviral therapy-related clearance of HCV RNA may occur both in patients with chronic HCV infection and in transplanted patients for HCV-related liver cirrhosis, but the role of the 5'-untranslated region (UTR) of HCV containing the internal ribosome entry site (IRES), which directs the translation of the viral open reading frame has not hitherto been evaluated. We studied the 5'-UTR in an HCV-infected recipient of a liver graft that showed spontaneous clearance of HCV RNA during an acute hepatitis B virus (HBV) superinfection. Sequencing of the 5'-UTR of HCV showed a nucleotide A insertion at position 193 of the IRES.
5' Untranslated Regions↗