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At least 919 records · Page 51Linked to original sources
PubMed2003

Polyomavirus allograft nephropathy: sequential assessment of histologic viral load, tubulitis, and graft function following changes in immunosuppression.

Our initial cases of polyoma virus allograft nephropathy (PVAN) received pulse steroids due to anxiety about concomitant acute rejection triggered by the presence of tubulitis. However, our current policy is to reduce immunosuppression in all cases. The aim of this study was to determine whether clinical follow-up in these patient categories shows any differences in: (a) histologic viral load, (b) grade of tubulitis, and (c) graft function. Reduced viral load assessed within 8 weeks was seen in 4/20 (20.0%) biopsies treated initially by increased immunosuppression, compared to 15/19 (83.3%) biopsies treated with reduced immunosuppression (p = 0.001, Fisher's exact test). Yet, >70% reversal of the rise in serum creatinine occurred in only 3/19 (15.8%) and 1/19 (5.3%) patients, respectively, in these two groups. Improved tubulitis was seen in 11/20 (55%) of biopsies treated with steroids, despite the lack of beneficial effect on serum creatinine in 12/19 (63.1%) instances. In biopsies not treated with any change in immunosuppression, the serum creatinine remained stable in 1/5 (20%) and worsened in 4/5 (80%) biopsies. These data demonstrate that in biopsies with PVAN and tubulitis, reduced immunosuppression is more effective in lowering viral load than steroid therapy. Lack of parallelism between viral load, tubulitis grade, and serum creatinine illustrates a complex interplay of viral and alloimmune factors leading to graft injury.

Adult↗
PubMed1994

Regulation of apoptosis in transgenic mice by simian virus 40 T antigen-mediated inactivation of p53.

Several proteins encoded by DNA tumor viruses are thought to disrupt cellular growth control by interacting with key cellular proteins, such as p53 and pRB, that normally function to regulate cell growth. However, the biological consequences of intracellular complexing between the viral oncoproteins and cellular proteins have remained unclear. Such complexes could either facilitate functional inactivation of the cellular proteins, leading to a loss-of-function phenotype, or could activate new functions, leading to a gain-of-function phenotype. Here we demonstrate that the simian virus 40 large tumor (T) antigen produces a loss-of-p53-function phenotype when introduced into the thymocytes of transgenic mice. Like thymocytes from the recently characterized p53-null mice, thymocytes from transgenic mice expressing a T-antigen variant capable of binding to p53 are resistant to irradiation-induced apoptosis. Thymocytes from transgenic mice expressing a mutant T antigen that is unable to complex p53, but retains the ability to complex the pRB and p107 proteins, retain sensitivity to irradiation. We further demonstrate that although irradiation-induced apoptosis is impaired by T antigen, clonal deletion of autoreactive thymocytes via p53-independent apoptosis is not perturbed by T antigen. These results provide convincing evidence that T antigen inactivates p53 in thymocytes in vivo and suggest a mechanism by which T antigen predisposes thymocytes to tumorigenesis in T antigen-transgenic mice.

Animals↗
PubMed1984

Role of recombinant ecotropic and polytropic viruses in the development of spontaneous thymic lymphomas in HRS/J mice.

The biological and genetic characteristics of murine leukemia viruses (MuLV) derived from leukemic and normal HRS/J mice were studied. T1-oligonucleotide fingerprinting and mapping of viral RNAs from unpassaged isolates revealed the presence of complex mixtures of viral genomes. MuLV that were purified by endpoint dilution were genetically heterogeneous. Thus, endogenous retroviral sequences expressed in the tissues of HRS/J mice readily recombined with one another. Furthermore, the regular recovery of recombinant ecotropic MuLV suggested reciprocal in vivo complementation of a genetic defect(s) in each of the endogenous ecotropic proviruses Emv-1 and Emv-3. Some recombinant ecotropic viruses contained sequences in the p15E-U3 region that were not derived from Emv-1 and Emv-3 but were found in recombinant polytropic HRS/J viruses. Finally, comparison of the genetic structures of leukemogenic and nonleukemogenic MuLV of this strain implied that the oncogenic phenotype of these MuLV is encoded within env or the U3 region of the genome or both. Our results are consistent with a stepwise convergent evolution of recombinant MuLV in vivo in individual HRS/J mice. Ultimately, this process of selection results in formation of leukemogenic polytropic viruses.

Animals↗
PubMed1993

Adenovirus E4orf4 protein binds to protein phosphatase 2A, and the complex down regulates E1A-enhanced junB transcription.

Adenovirus E4orf4 protein was previously shown to counteract transactivation of junB by cyclic AMP (cAMP) and E1A protein. It was also shown to cause hypophosphorylation of E1A and c-Fos proteins. Here we show that the E4orf4 protein associates with protein phosphatase 2A. All three subunits of the phosphatase are present in the complex, and the B subunit interacts directly with the viral protein. The complex possesses a phosphatase activity typical of protein phosphatase 2A, and the phosphatase mediates the E4orf4-induced down regulation of junB transcription. Thus, adenovirus E4orf4 protein recruits protein phosphatase 2A into a signal transduction pathway initiated by cAMP and E1A protein.

Adenovirus E1A Proteins↗
PubMedDate not supplied

Clinical importance of assessment of HBsAg/IgM complexes in chronic hepatitis B.

In serum of patients with chronic hepatitis B (HB) in the stage of active viral replication HBsAg/IgM complexes were detected. Using a commercial kit AU-IGM-K Sorin Biomedica HBsAg/IgM complexes in 136 patients with chronic HB and cirrhosis of the liver were examined, incl. 89 men, 42 women and 5 children, mean age 48 +/- 17 years. With regard to the results of the serological examination for HB virus (HBV) markers the results in 54 patients with positive HBeAg and HBsAg in serum (group 1) were compared with 68 patients with positive HBsAg only (group 2) and with 14 patients with positive antibodies against HBV or unrelated to HBV (group 3). The mean positivity index of HBsAg/IgM complexes in group 1, 2 and 3 was 9.89, 1.85 and 0.50, respectively. The results suggest a significant predominance of HBsAg/IgM complexes in patients during the stage of active viral replication with positive HBeAg in serum, as compared with patients without HBeAg (p = 0.001) and the control group (p = 0.001). A similar significant difference between groups was found as regards to ALT and AST activities. We conclude that in patients with chronic HBeAg positive hepatitis and a moderately elevated transaminase activity usually also HBsAg/IgM complexes, which are closely correlated with HBeAg, are positive.

Adolescent↗
PubMed1993

Presentation of numerous viral peptides to mouse major histocompatibility complex (MHC) class I-restricted T lymphocytes is mediated by the human MHC-encoded transporter or by a hybrid mouse-human transporter.

The major histocompatibility complex-encoded transporter associated with antigen processing (TAP) is required for the efficient presentation of cytosolic antigens to class I-restricted T cells. TAP is thought to be formed by the interaction of two gene products, termed TAP1 and TAP2. We find that TAPs consisting either of human subunits, or mouse TAP1 and human TAP2, facilitate the presentation of numerous defined viral peptides to mouse class I-restricted T cells. As human and mouse TAP2 and TAP1 differ in 23 and 28% of their residues, respectively, this indicates that TAP1 and TAP2 can form a functional complex with partners considerably different from those they coevolved with. Moreover, these findings indicate that widely disparate TAPs facilitate delivery of the same peptides to class I molecules. These findings suggest that TAP polymorphism does not greatly influence the types of peptides presented to the immune system.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1996

Structure of the complex between human T-cell receptor, viral peptide and HLA-A2.

Recognition by a T-cell antigen receptor (TCR) of peptide complexed with a major histocompatibility complex (MHC) molecule occurs through variable loops in the TCR structure which bury almost all the available peptide and a much larger area of the MHC molecule. The TCR fits diagonally across the MHC peptide-binding site in a surface feature common to all class I and class II MHC molecules, providing evidence that the nature of binding is general. A broadly applicable binding mode has implications for the mechanism of repertoire selection and the magnitude of alloreactions.

Crystallography, X-Ray↗
PubMed1997

Expression and purification of vesicular stomatitis virus N-P complex from Escherichia coli: role in genome RNA transcription and replication in vitro.

The nucleocapsid protein (N) and phosphoprotein (P) genes of vesicular stomatitis virus (VSV), Indiana serotype, were coexpressed in Escherichia coli BL21(DE3) by using the expression vector pET-3a. The coexpression resulted in the formation of N-P complex. The purified N-P complex was found to inhibit transcription in vitro mediated by viral ribonucleoprotein (RNP) complex in a dose-dependent manner. However, addition of uninfected mammalian cell extracts together with the N-P complex to the transcribing RNP resulted in the synthesis of full-length negative-strand genome RNA. These results indicate that the N-P complex regulated transcription and a cellular factor(s) in combination with the N-P complex may switch the RNA polymerase from transcription to replication mode.

Cloning, Molecular↗
PubMed1987

The inhibitory effect of dithiothreitol on the assembly of the filamentous phage fd.

Assembly of the filamentous phage fd is preceded by the formation of a complex between the viral single-stranded (ss) DNA and the virally coded gene 5 protein (gene 5 protein-ssDNA complex). The presence of 5 mM dithiothreitol in the growth medium prevents phage production; however, phage infection, phage DNA replication and phage genome expression are still observed. In contrast, the gene 5 protein-ssDNA complex is not formed in the presence of dithiothreitol in vivo, although the complex is not affected by the disulfide reducing agent in vitro. Furthermore, host lipid composition is altered by growth in the presence of dithiothreitol. The zwitterionic lipid, phosphatidylethanolamine, increases while the cationic phospholipid content, cardiolipin and phosphatidylglycerol, decreases. This suggests a role for lipids or membranous structures in the process of gene 5 protein-ssDNA complex formation.

Cardiolipins↗
PubMedDate not supplied

[Local express auto-cytokine therapy (a complex of cytokines) in the treatment of viral and nonviral eye lesions].

The method of local express-autocytocinetherapy (LEACCT) consists in using an experimentally tested autologous complex of cytokines (alpha- beta- gamma-interferons, interleukins 2.8, tumor necrosis factor gamma etc.), which is produced by joining the autoblood of patients with immune-modulator poludan (complex poly A:poly U). The external LEACCT and the intrachamber LEACCT are distinguished. The former presupposes the administration (subconjunctivally and in installations) of the autoblood-poludan mixture. This method is used in herpes- and adenovirus keratoconjunctivitis, slow re-epithelization after laser keratectomy and in eye burns (178 patients). The latter comprises, apart from the external LEACCT procedures, a 1-4-time introduction of the mentioned mixture into patient's anterior chamber. It was used in endothelial herpetic keratoiridocyclitis, initial bullous keratopathy, severe keratoconus and in injuries of the anterior lens capsule (117 patients). The clinical-study results (main group--295 patients) show that the designed method based on poludan has pronounced anti-inflammatory and regenerative effects in different viral and virus-free lesions of the eye tissues; it is simple and can be applied in clinical settings. An increased visual acuity ranging from 0.05 to 1.0 was registered in 85% of cases. The action of the complex of cytokines is as close as possible to the physiological mechanism, which provides for avoiding the side-effects and for applying the treatment scheme in situations when the administration of other drugs is limited or their efficiency is not sufficient.

Adenoviridae Infections↗
PubMed1992

The structure of the complex between influenza virus neuraminidase and sialic acid, the viral receptor.

Crystallographic studies of neuraminidase-sialic acid complexes indicate that sialic acid is distorted on binding the enzyme. Three arginine residues on the enzyme interact with the carboxylate group of the sugar which is observed to be equatorial to the saccharide ring as a consequence of its distorted geometry. The glycosidic oxygen is positioned within hydrogen-bonding distance of Asp-151, implicating this residue in catalysis.

Fourier Analysis↗
PubMed1983

Dissociation of the Pf1 nucleoprotein assembly complex and characterisation of the DNA binding protein.

During replication of bacteriophage Pf1, progeny viral strands are complexed with a single-stranded DNA binding protein, analogous to the gene 5 protein of bacteriophage fd. Using fluorescence spectroscopy, ultracentrifugation and DNA-cellulose chromatography, conditions for dissociation of the nucleoprotein have been investigated. The Pf1 protein is unusual in that it is not released from the DNA by 2 M NaCl. Complete separation occurs in 0.6-1.0 M MgCl2, leading to a procedure for the purification of the protein. Two subfractions of the protein can be isolated of isoelectric points 5.9 and 6.4. The molecular weight of the native DNA binding protein has been studied by gel filtration and sedimentation. The major species in solution has a sedimentation coefficient of 2.3 S and a diffusion coefficient of 7.8 X 10(-7) cm2 . s-1, corresponding to a protein dimer (Mr = 30 800). Protein tetramers are induced in the presence of octanucleotides, but not tetranucleotides. Analysis of the ultraviolet spectra of the DNA binding protein and the native nucleoprotein complex indicates a stoichiometry of 3.9 +/- 0.4 nucleotides per protein subunit. The molar extinction coefficient of the DNA when bound to the protein (epsilon 260 = 8100) suggests that the binding protein maintains the DNA in an extended (unstacked) conformation similar to that found in the mature Pf1 virion.

Bacteriophages↗
PubMed2026

Viral inhibition of the anaphase promoting complex enhances replication by elevating nucleotide pools.

The anaphase promoting complex/cyclosome (APC/C) is a large, ubiquitin ligase and a central regulator of cell cycle progression. By targeting key substrates for degradation during mitosis and G1 phase, the APC/C coordinates metabolic fluctuations that occur during the cell cycle. A diverse range of viruses have convergently evolved mechanisms to bind and inhibit the APC/C; however, a molecular understanding for these interactions has never been demonstrated. Here, we use chicken anemia virus (CAV), a small single-stranded DNA virus encoding only three proteins, to demonstrate the importance of viral APC/C inhibition during replication. We show that the Vp3 protein of CAV inhibits the APC/C, causing a dramatic mitotic arrest during infection. The mutant virus lacking Vp3 is defective for replication and can be rescued by APC/C inhibition. Metabolomic profiling during CAV infection revealed that Vp3 expression mediates a broad increase in nucleotide pools. Moreover, viral inhibition of the APC/C resulted in stabilization of enzymes required for nucleotide biosynthesis. These findings suggest that the APC/C is a general target of many viruses to elevate nucleotide levels and facilitate viral genome replication.

Anaphase-Promoting Complex-Cyclosome↗
PubMed2004

Dissociation of CD4(+) cell counts from viral load and association with immune complexes in HIV(+) hemophilia patients.

OBJECTIVE: We have postulated that the host autoimmune response regulates and mediates CD4 depletion during HIV infection by opsonization of circulating CD4(+) lymphocytes carrying autoreactive immune complexes (IC) consisting of complement-fixing IgM and IgG, and during advanced stages of HIV disease of IgM/ IgG/gp120 complexes. In this retrospective study, we investigated whether HIV causes CD4 depletion by direct cytotoxicity or indirectly by induction of a host autoimmune response. PATIENTS AND METHODS: In 1996, 12 HIV(+) hemophilia patients were converted to highly active antiretroviral therapy (HAART), while 10 other patients were maintained on conventional antiretroviral treatment and another 11 patients refused to be treated with antiretroviral drugs. The host immune response of these 33 HIV(+) patients was studied during the periods of minimum viral replication (Interval 1), subsequent rise in viral replication with strong replication dynamic (Interval 2), and maximum viral replication (Interval 3). The patients were categorized into three groups according to viral load (VL). Group A: patients with low level VL (n=10) showed a modest increase from <80 to <4 log 10 HIV-1 RNA copies per milliliter plasma during the observation period; Group B: patients with medium level VL (n=12) showed a stronger increase from <80 to >4 log 10 copies per milliliter plasma; and Group C: patients with high level VL (n=11) consistently had a median of >4 log 10 copies per milliliter plasma, during Intervals 1-3, with the exception of one patient who during Interval 2 had 4800 copies per milliliter. Blood lymphocyte subpopulations, proportions of CD4(+) blood lymphocytes coated with IgM, IgG, C3d and/or gp120, in vitro responses to mitogens and pooled allogeneic stimulator cells, as well as numbers of HIV-1 RNA copies per milliliter plasma were measured. RESULTS: Sequential analysis of VL, IC load on CD4(+) blood lymphocytes and CD4 counts showed that an increasing VL was not associated with CD4 depletion, when the proportion of IC-coated circulating CD4(+) blood lymphocytes remained stable. When, CD4 counts and IC load were analyzed during corresponding intervals of retroviral replication in the three patient groups, a higher VL was associated with lower CD4 counts only when the IC load (IgG or gp120/IgG) on CD4(+) lymphocytes was higher as well. CONCLUSION: These data suggest that HIV regulates and mediates CD4 depletion in part by the induction of autoreactive ICs against CD4(+) lymphocytes, especially complement-fixing autoreactive IgG and gp120/IgG complexes.

CD4 Antigens↗
PubMed1986

Circulating immune complexes in patients with subacute sclerosing panencephalitis.

Levels of immune complexes (ICs) in serum and cerebrospinal fluid (CSF) specimens from subacute sclerosing panencephalitis (SSPE) patients were measured using a solid-phase C1q radioimmunoassay. Single or serial serum specimens were available from 19 patients, while serial CSF specimens were available from two patients. ICs isolated from one CSF specimen by C1q immobilized to Affi-Gel were analyzed for measles virus antigens by binding of measles virus-specific antisera and by polyacrylamide gel electrophoresis followed by Western blotting. Of 78 serum specimens analyzed, 36 (46%) were positive for ICs. When the 8 patients with 3 or more serum specimens were analyzed, 6 had fluctuating levels of ICs. Two of 5 CSF specimens obtained from a patient during acute disease onset were IC-positive, while a second patient exhibited a rapid increase and decrease of IC levels in 14 CSF specimens obtained during an acute disease exacerbation. Composition analysis of ICs isolated from one of the CSF specimens revealed the presence of antigens corresponding in size to measles virus polymerase, nucleoprotein, and possibly, hemagglutinin polypeptides. These results show that SSPE patients frequently have ICs, that IC levels fluctuate in both serum and CSF, and that the ICs are at least partially composed of measles virus antigens.

Antigen-Antibody Complex↗