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At least 235 records · Page 13Linked to original sources
PubMed2003

Immunopathogenesis of hepatitis C virus infection.

HCV infection becomes persistent in many patients who are otherwise immune competent. There is increasing support for potential contribution of innate immune response and viral interference with its components to the subsequent outcome. As for the adaptive immune response, humoral immunity may be largely ineffective despite evidence for neutralizing antibody response directed to the E2 HVR region, perhaps due to rapid selection of antibody escape variants. Cellular immune response does seem to play a role in the virologic outcome during acute infection based on strong association of a sustained vigorous and multispecific antiviral CD4 and CD8 T cell response with HCV clearance during acute infection. Following clearance, vigorous CD4 T cell response to HCV is maintained for many years, whereas the memory CD8 T cell response may be maintained with variable efficiency. If unable to clear the virus quickly, the T cell response (particularly if focused) may also select for T cell escape variants that are poorly recognized by the circulating T cells or even actively inactivate them through T cell antagonism. In established chronic infection. HCV-specific T cell response is quantitatively weak, providing only minimal selection pressure for further escape mutation. Although earlier studies using conventional in vitro techniques suggest that this low-frequency T cell response may help control the virus and liver disease progression, the role and nature of these apparently defective T cells in the outcome of chronic HCV infection remains to be fully determined. In summary, much progress has been made in the field of HCV immune pathogenesis since the initial identification of HCV. Although more work is needed to define the mechanism of HCV persistence and liver cell injury, there is considerable hope as well as challenge for potential development of vaccine and immunotherapy for HCV infection (see article by Drs. Inchaupsé and Feinstone). A better understanding of the relevant host and viral factors for clinical and virologic outcome, and the mechanism of selective immune defect against HCV, will be invaluable in our ability to treat the many patients infected with HCV.

Animals↗
PubMed2005

Immune evasion by hepatitis C virus NS3/4A protease-mediated cleavage of the Toll-like receptor 3 adaptor protein TRIF.

Toll-like receptors (TLRs) bind pathogen-specific ligands early in infection, initiating signaling pathways that lead to expression of multiple protective cellular genes. Many viruses have evolved strategies that block the effector mechanisms induced through these signaling pathways, but viral interference with critical proximal receptor interactions has not been described. We show here that the NS3/4A serine protease of hepatitis C virus (HCV), a virus notorious for its ability to establish persistent intrahepatic infection, causes specific proteolysis of Toll-IL-1 receptor domain-containing adaptor inducing IFN-beta (TRIF or TICAM-1), an adaptor protein linking TLR3 to kinases responsible for activating IFN regulatory factor 3 (IRF-3) and NF-kappaB, transcription factors controlling a multiplicity of antiviral defenses. NS3/4A-mediated cleavage of TRIF reduces its abundance and inhibits polyI:C-activated signaling through the TLR3 pathway before its bifurcation to IRF-3 and NF-kappaB. This uniquely broad mechanism of immune evasion potentially limits expression of multiple host defense genes, thereby promoting persistent infections with this medically important virus.

Adaptor Proteins, Vesicular Transport↗
PubMed1998

Relationship of serum markers of hepatitis B and C virus replication in coinfected patients.

To evaluate viral interference between hepatitis B and C, we studied coinfected patients serologically and molecular biologically. Twenty-seven patients positive for hepatitis B surface antigen (HBsAg) and anti-hepatitis C virus (HCV) antibody, were classified into Groups BC-L and BC-H according to DNA-polymerase activity (less or greater than 100 cpm, respectively). Patients with hepatitis B or C alone were also enrolled as controls. HCV-RNA was detected more often in Group BC-L than in Group BC-H. Genotype 1b of HCV was determined in 75% of Group BC-H, 87.5% of Group BC-L, and 70.7% of hepatitis C-only patients. Activity of DNA-polymerase in coinfected patients was lower in patients positive for HCV-RNA as compared with those negative. HBsAg titers tended to be lower in coinfected patients than in patients with hepatitis B virus (HBV) alone. In conclusion, in coinfection, HBV may suppress the replication of HCV and HCV appears to reduce the expression of HBsAg and probably suppresses HBV replication.

Adult↗
PubMed2005

Processes of diversification and dispersion of rice yellow mottle virus inferred from large-scale and high-resolution phylogeographical studies.

Phylogeography of Rice yellow mottle virus (RYMV) was reconstructed from the coat protein gene sequences of a selection of 173 isolates from the 14 countries of mainland Africa where the disease occurred and from the full sequences of 16 representative isolates. Genetic variation was linked to geographical distribution and not to host species as isolates from wild rice always clustered with isolates from cultivated rice of the same region. Genetic variation was not associated to agro-ecology, viral interference and insect vector species. Distinct RYMV lineages occurred in East, Central and West Africa, although the Central African lineage included isolates from Benin, Togo and Niger at the west, adjacent to countries of the West African lineage. Genetic subdivision at finer geographical scales was apparent within lineages of Central and West Africa, although less pronounced than in East Africa. Physical obstacles, but also habitat fragmentation, as exemplified by the small low-lying island of Pemba offshore Tanzania mainland, explained strain localization. Three new highly divergent strains were found in eastern Tanzania. By contrast, intensive surveys in Cote d'Ivoire and Guinea at the west of Africa did not reveal any new variant. Altogether, this supported the view that the Eastern Arc Mountains biodiversity hotspot was the centre of origin of RYMV and that the virus spread subsequently from east to west across Africa. In West Africa, specific strains occurred in the Inner Niger Delta and suggested it was a secondary centre of diversification. Processes for diversification and dispersion of RYMV are proposed.

Africa↗
PubMed1981

Detection of a recombinant murine leukemia virus-related glycoprotein on virus-negative thymoma cells.

X-irradiation of outbred Swiss mice resulted in the development of virus-free thymomas. When put in culture, a lymphoblastic cell line (NIXT) expressed neither particles nor infectious virus but supported the growth of pure ecotropic murine leukemia viruses (MuLVs) without generating any envelope recombinant (RM) MuLV in more than 20 months of culture. These cells did not support the growth of RM-MuLVs and completely excluded the entry of all RM-MuLV pseudotypes of murine sarcoma virus, suggesting specific viral interference. Radioimmunocompetition and immunofluorescence assays with broadly reactive anti-MuLV-p30 and -gp70 antisera were negative. However, in immunofluorescence with antisera specifically reactive against RM-MuLV gp70, about 5-20% of the population of parental cells or their clones were positive. NIXT cells treated with this antiserum bound protein A and exhibited complement-dependent cytotoxicity as assessed by several assays. NIXT cells could partially absorb neutralizing antibody specific for RM-MuLVs. Based on radioimmunoprecipitation tests, NIXT cells bore, on the cell surface, a glycosylated protein (gp70) reactive with RM subgroup as well as some group-specific anti-gp70 antisera. The glycoprotein was also found free in the supernates of NIXT cells. Using affinity chromatography, we determined the peptide pattern of the gp70 from NIXT cells to determine its structural relationship to gp70s of other MuLVs. NIXT gp70 was found to be highly related to class III endogenous xenotropic gp70s but, in addition, had peptide characteristics of RM-gp70s. Apparently, NIXT cells code for an unusual gp70 protein in the absence of other MuLV expression. The possible role of this glycoprotein in leukemogenesis is discussed.

Animals↗
PubMed1987

Molecular characterization of the Akvr-1 restriction gene: a defective endogenous retrovirus-borne gene identical to Fv-4r.

A dominant restriction allele, Akvr-1r, from California wild mice (Mus musculus domesticus) confers resistance to exogenous ecotropic murine leukemia virus (MuLV) infection. The presence of an ecotropic MuLV envelope-related glycoprotein in uninfected virus-resistant cells suggests that viral interference is a possible mechanism for this resistance. We molecularly cloned the ecotropic MuLV envelope-related sequence from the genomic DNA of a wild mouse homozygous for the Akvr-1r locus. The cloned provirus was defective and contained a C-terminal end of the pol gene, a complete envelope gene, and a 3' long terminal repeat. The presence of this provirus was directly correlated with Akvr-1r-mediated virus resistance in cell cultures and hybrid mice. The Akvr-1r provirus restriction map and partial DNA sequence were identical to those of the Fv-4r allele, an ecotropic MuLV resistance locus from Japanese feral mice (M. musculus molossinus), which was previously shown to be allelic with the Akvr-1r gene. The 3' host flanking sequences of Fv-4r and Akvr-1r also had identical restriction maps. These findings indicate that Akvr-1r and Fv-4r are the same gene. It was probably acquired by interbreeding of these feral species in recent times. Conservation of this locus might be favored by the useful function that it performs in protection against ecotropic MuLV infection endemic in both populations of wild mice.

Alleles↗
PubMed1998

Pathogenicity induced by feline leukemia virus, Rickard strain, subgroup A plasmid DNA (pFRA).

A new provirus clone of feline leukemia virus (FeLV), which we named FeLV-A (Rickard) or FRA, was characterized with respect to viral interference group, host range, complete genome sequence, and in vivo pathogenicity in specific-pathogen-free newborn cats. The in vitro studies indicated the virus to be an ecotropic subgroup A FeLV with 98% nucleotide sequence homology to another FeLV-A clone (F6A/61E), which had also been fully sequenced previously. Since subgroup B polytropic FeLVs (FeLV-B) are known to arise via recombination between ecotropic FeLV-A and endogenous FeLV (enFeLV) env elements, the in vivo studies were conducted by direct intradermal inoculation of the FRA plasmid DNA so as to eliminate the possibility of coinoculation of any FeLV-B which may be present in the inoculum prepared by propagating FeLV-A in feline cell cultures. The following observations were made from the in vivo experiments: (i) subgroup conversion from FeLV-A to FeLV-A and FeLV-B, as determined by the interference assay, appeared to occur in plasma between 10 and 16 weeks postinoculation (p.i.); (ii) FeLV-B-like recombinants (rFeLVs), however, could be detected in DNA isolated from buffy coats and bone marrow by PCR as early as 1 to 2 weeks p.i.; (iii) while a mixture of rFeLV species containing various amounts of N-terminal substitution of the endogenous FeLV-derived env sequences were detected at 8 weeks p.i., rFeLV species harboring relatively greater amounts of such substitution appeared to predominate at later infection time points; (iv) the deduced amino acid sequence of rFeLV clones manifested striking similarity to natural FeLV-B isolates, within the mid-SU region of the env sequenced in this work; and (v) four of the five cats, which were kept for determination of tumor incidence, developed thymic lymphosarcomas within 28 to 55 weeks p.i., with all tumor DNAs harboring both FeLV-A and rFeLV proviruses. These results provide direct evidence for how FeLV-B species evolve in vivo from FeLV-A and present a new experimental approach for efficient induction of thymic tumors in cats, which should be useful for the study of retroviral lymphomagenesis in this outbred species.

3T3 Cells↗
PubMed1970

Interferons.

Explore the source record for details and available documents.

Endotoxins↗
PubMed2006

S-Adenosylmethionine and betaine correct hepatitis C virus induced inhibition of interferon signaling in vitro.

Hepatitis C virus (HCV) infection is an important cause of chronic liver disease. Standard therapy, pegylated interferon alpha (pegIFNalpha) combined with ribavirin, results in a sustained response rate in approximately half of patients. The cause of treatment failure in the other half of the patients is unknown, but viral interference with IFNalpha signal transduction through the Jak-STAT pathway might be an important factor. We have shown previously that the expression of HCV proteins leads to an impairment of Jak-STAT signaling because of an inhibition of STAT1 methylation. Unmethylated STAT1 is less active because it can be bound and inactivated by its inhibitor, protein inhibitor of activated STAT1 (PIAS1). We show that treating cells with S-adenosyl-L-methionine (AdoMet) and betaine could restore STAT1 methylation and improve IFNalpha signaling. Furthermore, the antiviral effect of IFNalpha in cell culture could be significantly enhanced by the addition of AdoMet and betaine. In conclusion, we propose that the addition of these drugs to the standard therapy of patients with chronic hepatitis C could overcome treatment resistance.

Adenosine↗
PubMed1994

Characterization of the human papillomavirus E2 protein: evidence of trans-activation and trans-repression in cervical keratinocytes.

The major regulator of papillomavirus transcription is encoded by the viral E2 gene. The E2 gene has been well characterized in bovine papillomavirus (BPV) where it encodes at least three different polypeptides which differentially affect viral gene expression. In human papillomaviruses (HPVs) the E2 gene product is much less well characterized. In this study we have analysed the mechanism of action of the HPV-16, HPV-18 and BPV-1 E2 proteins in cervical keratinocytes. We show that the full length HPV E2 protein acts as a potent transcriptional activator of viral gene expression in both normal and immortalized keratinocytes. In contrast, the BPV-1 E2 protein produces transcriptional repression under identical conditions. A cDNA encoding the C-terminal half of the HPV-16 E2 protein in these assays weakly repressed viral gene expression. Further, co-transfection of this cDNA with the full length clone progressively abolishes the activation in trans by the full length HPV E2 protein. Gel retardation assays have defined a number of protein complexes between the long and short forms of E2 but with no evidence for preferential DNA binding. These results define two distinct activities for the HPV-16 E2 protein, indicate functional differences with the BPV E2 protein and suggest that splicing of the HPV E2 mRNA is a critical mechanism for controlling viral gene expression.

Animals↗
PubMed1986

Interferon-mediated self-limiting growth of respiratory syncytial virus in mouse embryo cells.

The growth of respiratory syncytial (RS) virus in primary mouse embryo (ME) cells was investigated. The virus yields in ME cells were markedly lower if compared with those in HEp-2 cells, which are fully permissive for RS virus, and a remarkable production of interferon (IFN) was found in the early period of infection of the former cells. The virus yields in ME cells were enhanced when antimouse IFN serum was added to the medium. Indirect immunofluorescent staining of infected ME cells showed that the infection spread in the entire monolayer in the presence of antiserum, whereas it was markedly restricted throughout in the absence of the serum. All the major viral polypeptides were synthesized in the absence of the serum. However, their synthesis rates were greatly enhanced if the antiserum was added. These results suggest that the virus growth in ME cells is self-limiting and that this limited growth is due to autointerference by endogenously produced IFN during the course of infection. Further, this type of growth restriction of RS virus appears to be characteristic of cells of mouse origin by comparative studies that used other cells of different origin.

Animals↗
PubMed1995

Phage HK022 Nun protein arrests transcription on phage lambda DNA in vitro and competes with the phage lambda N antitermination protein.

Phage HK022 Nun protein excludes phage lambda by terminating transcription near the lambda nut sites. We have established a purified in vitro system that reproduces the in vivo sequence and factor requirements of Nun. Nun arrests transcription by E. coli RNA polymerase at or near elongation pause sites distal to the nut sites. The boxB sequence of nut is required for optimal Nun activity; boxA plays a lesser role. The efficiency of transcription arrest is strongly enhanced by the four E. coli Nus factors. The factors increase the specific activity of Nun, and allow it to act at higher ribonucleoside triphosphate concentrations. A wild-type boxA is required for stimulation by Nus factors. Nun and the lambda N antitermination protein compete for their opposing reactions. This competition may be at the level of binding of boxB RNA.

Bacterial Proteins↗
PubMed1993

Resistance and susceptibility of bovine cells expressing herpesviral glycoprotein D homologs to herpesviral infections.

Bovine cell lines individually expressing two related herpesviral proteins, pseudorabies virus glycoprotein 50 and herpes simplex virus type 1 glycoprotein D, were examined for their susceptibility/resistance to infection with several alphaherpesviruses. Cell lines expressing gp50 or gD-1 resisted plaque formation by the homologous virus more than by the heterologous viruses. Bovine cells expressing bovine herpesvirus 1 glycoprotein IV (gIV) were susceptible to infection with three other bovine herpesviruses: bovine herpesvirus 2, bovine herpesvirus 4 (BHV-4) and alcelaphine herpesvirus 1. One line of gIV-expressing cells was resistant to the formation of BHV-4 plaques, suggesting that a cell-associated factor may be responsible for inhibiting cell-to-cell spread.

Animals↗
PubMed1994

A 55-kDa protein induced in Aedes albopictus (mosquito) cells by antiviral protein.

We have previously shown that the antiviral protein (AVP) produced by Sindbis virus-infected Aedes albopictus (mosquito) cells (Riedel and Brown, J. Virol. 29, 51-60, 1979) blocks Sindbis viral RNA synthesis and stimulates its own production when applied to uninfected A. albopictus cells (Luo and Brown, Virology 194, 44-49, 1993). From a virus-sensitive (wild-type) mosquito cell line (U4.4) we produced a virus-resistant cell line (L4.4) by exposing U4.4 cells to the AVP. L4.4 cells constitutively produce AVP and fail to replicate viral RNA after infection with virus or transfection with purified viral RNA. In this study we have compared cellular proteins produced as the sensitive cells are temporally converted to the resistant phenotype following exposure to the AVP. A 55-kDa membrane protein associated with lysosomes is found in L4.4 and not in U4.4 cells. This protein is induced during the first 48 hr following treatment of U4.4 cells with the AVP. The correlation of the appearance of the 55-kDa protein with the onset of virus resistance implies that this AVP-induced protein may be responsible for the inhibition of viral RNA replication. Although virus RNA synthesis is blocked in the L4.4 cell line, we have found that the synthesis of nonstructural proteins takes place.

Aedes↗
PubMed1996

CfMNPV blocks AcMNPV-induced apoptosis in a continuous midgut cell line.

Morphological and molecular changes produced by Autographa californica nuclear polyhedrosis virus (AcMNPV) infection in a permissive cell line, IPLB-SF-21AE (SF-21), of Spodoptera frugiperda and a nonpermissive cell line, FPMI-CF-203 (CF-203), of Choristoneura fumiferana are described. CF-203 cells inoculated with AcMNPV showed a DNA ladder and morphological changes such as plasma membrane granulation, blebbing, and nuclear fragmentation, which are characteristic of apoptosis. Typical virus replication and occlusion body (OB) production were seen in SF-21 cells inoculated with AcMNPV and no apoptosis-like symptoms were observed. mRNA for the apoptosis suppressor gene p35 was detected 9 hr later in AcMNPV-inoculated CF-203 cells than in SF-21 cells. Only a trace amount of mRNA for the AcMNPV-inhibitor of apoptosis homologue (Ac-iap) gene and no mRNAs for the late genes, AcMNPV-polyhedrin (Ac-polh) and AcMNPV-p10 (Ac-p10), were detected in AcMNPV-inoculated CF-203 cells. Inoculation of CF-203 cells with CfMNPV at least 12 hr prior to inoculation with AcMNPV prevented apoptosis-like cell death, and mRNAs for Ac-iap, Ac-polh, and Ac-p10 genes were expressed resulting in successful virus replication and OB production.

Animals↗
PubMed1998

Inhibition/stimulation of bovine papillomavirus by adeno-associated virus is time as well as multiplicity dependent.

Infection by adeno-associated virus (AAV) is associated with lower cervical cancer rates. We have been investigating the hypothesis that AAV interacts with and inhibits the role of human papillomaviruses (HPV) in cervical cancer. We have been studying the response of bovine papillomavirus type 1 (BPV) oncogenic transformation and DNA replication to AAV as a prototype system. The AAV Rep 78 gene product is responsible for this inhibition. Here, it is demonstrated that in two assay systems, focus formation of C127 cells and chloramphenicol acetyl-transferase (CAT, measuring P89 promoter expression) assays, the smaller the time interval between AAV introduction relative to BPV introduction, the higher the level of inhibition resulted. Preinfection with AAV was also effective in inhibiting BPV, but the effectiveness also decreased with increasing time intervals. These differences in inhibition demonstrate that the efficiency of AAV's inhibition of BPV changes dramatically with time (as much as 10(4) when delaying AAV infection) and possibly reflect temporal changes in viral gene expression by AAV, BPV, or both, which affect the AAV-papillomavirus interaction. It is further found that two different chimeric BPV/AAV genomes, equivalent to a specific simultaneous infection by these viruses at a specific ratio (which can't be duplicated by virus infection), were fully defective for oncogenic transformation and DNA replication. These chimeric BPV/AAV genomes were also able to trans-inhibit the wild-type BPV genome. Finally, and surprisingly, C127 cells with resident AAV Rep78 positive provirus were found to have increased sensitivity to oncogenic transformation by BPV. These data define the conditions under which an inhibitory affect of the AAV Rep78 gene on BPV phentotypes can be expected. However, under certain conditions AAV appears able to stimulate BPV oncogenic transformation. This final observation is not totally unexpected as Rep78 is a transcription factor known to both stimulate or repress AAV's own gene expression depending upon adenovirus coinfection.

Animals↗