Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.7.7.49 (reverse transcriptase)
31,746 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Incubation of the human T cell lymphotropic virus (HTLV)-IIIB and HTLV-RF strains of human immunodeficiency virus type 1 (HIV-1) with normal seronegative human serum under conditions that allow complement activation resulted in enhancement of infection of the MT2 human T cell line cultured in the presence of low amounts of virus. Infection of MT2 cells was assessed by measuring reverse transcriptase activity in supernatants at day 9 of culture. Complement activation by viral suspensions occurred through the alternative pathway. Opsonization of HTLV-RF viral particles with complement was sufficient to allow a productive infection to occur in cells exposed to suboptimal amounts of virus. Infection of MT2 cells with suboptimal amounts of serum-opsonized HIV-1 was suppressed by blocking the C3dg receptor (CR2, CD21) on MT2 cells with monoclonal anti-CR2 antibody and rabbit F(ab')2 anti-mouse immunoglobulin antibodies. Blocking of the gp120-binding site on CD4 under similar experimental conditions had no inhibitory effect on infection of MT2 cells with opsonized virus. Opsonization of HIV-1 with seronegative serum also resulted in a CR2-mediated enhancement of the infection of normal peripheral blood mononuclear cells and T lymphocytes. These results indicate that complement in the absence of antibody may enhance infection of C3 receptor-bearing T cells with HIV-1, and that the interaction of opsonized virus with the CR2 receptor may result by itself in the infection of target T cells in a CD4- and antibody-independent fashion.
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PMID:Complement mediates human immunodeficiency virus type 1 infection of a human T cell line in a CD4- and antibody-independent fashion. 182 39

The expression of CD4 antigen on the surface of LeuM3-positive human blood monocytes was found to be variable with 65 to 90% of cells from 46 normal human volunteers being positive by dual staining flow cytometry. When monocytes adhered to plastic (but not when cultured on Teflon), a marked decrease in CD4 expression was observed between 1 and 24 h post-adherence. CD4 expression could not be detected in macrophages adhered to plastic for 5 days by using four anti-CD4 monoclonal antibodies in flow cytometry or direct immunofluorescence. Conversely an increasing proportion of adherent cells expressed LeuM3 and OKM5 surface antigens over the 5 days. CD4 mRNA levels were measured by slot-blot and Northern hybridization, and total cellular CD4 protein levels by immunoprecipitation. Both cellular mRNA and CD4 levels remained constant throughout the 5 day period but membrane CD4 protein levels were greatly reduced indicating that the down-regulation of CD4 was post-translational. Infection with two of six fresh human immunodeficiency virus (HIV) isolates showed different kinetic patterns when tested on purified monocytes recently adhered to plastic and macrophages adherent for 5 days. HIV antigen and reverse transcriptase levels in infected monocyte cultures remained high for 3 to 4 weeks before detachment and necrosis of the cells occurred. Infection of macrophages generated much lower levels of antigen and reverse transcriptase which declined to very low or undetectable levels over 2 weeks, leaving persisting viable macrophages. One week after infection HIV nucleic acid was detected in 69 +/- 7% of monocytes and 6 +/- 3% of macrophages by in situ hybridization. Blocking experiments with anti-Leu3a monoclonal antibody suggested that HIV infection of 5 day adherent macrophages occurred mainly by a mechanism other than binding to CD4.
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PMID:Variations in CD4 expression by human monocytes and macrophages and their relationships to infection with the human immunodeficiency virus. 267 36

Novel molecular approaches to inhibit human immunodeficiency virus type 1 (HIV-1) infection have received increasing attention because of the lack of effective antiviral drug therapies in vivo. We now demonstrate that cells can be intracellularly immunized by cytoplasmic expression of single-chain variable antibody fragments (SFv) which bind to the HIV-1 reverse transcriptase (RT) enzyme. The expression of anti-RT SFv in T-lymphocytic cells specifically neutralizes the RT activity in the preintegration stage and affects the reverse transcription process, an early event of the HIV-1 life cycle. Blocking the virus at these early stages dramatically decreased HIV-1 propagation, as well as the HIV-1-induced cytopathic effects in susceptible human T lymphocytes, by impeding the formation of the proviral DNA. These data also demonstrate that intracellular, complete SFvs may gain access to viral proteins of the HIV-1 preintegration complex. These SFvs will provide a tool with which to better understand the molecular mechanisms involved in restricting viral replication in HIV-1-infected cells.
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PMID:Targeting human immunodeficiency virus type 1 reverse transcriptase by intracellular expression of single-chain variable fragments to inhibit early stages of the viral life cycle. 864 70

Blocking CD28-B7 T-cell costimulation by systemic administration of CTLA4Ig, a fusion protein which binds B7 molecules on the surface of antigen-presenting cells, prevents rejection and induces tolerance in experimental acute allograft rejection models. We tested the effect of CTLA4Ig therapy on the process of chronic renal allograft rejection using an established experimental transplantation model. F344 kidneys were transplanted orthotopically into bilaterally nephrectomized LEW recipients. Control animals received low dose cyclosporine for 10 days posttransplantation. Administration of a single injection of CTLA4Ig on day 2 posttransplant alone or in addition to the low dose cyclosporine protocol resulted in improvement of long-term graft survival as compared with controls. More importantly, control recipients which received cyclosporine only developed progressive proteinuria by 8-12 weeks, and morphological evidence of chronic rejection by 16-24 weeks, including widespread transplant arteriosclerosis and focal and segmental glomerulosclerosis, while animals treated with CTLA4Ig alone or in addition to cyclosporine did not. Competitive reverse transcriptase-PCR and immunohistological analysis of allografts at 8, 16, and 24 weeks showed attenuation of lymphocyte and macrophage infiltration and activation in the CTLA4Ig-treated animals, as compared with cyclosporine-alone treated controls. These data confirm that early blockade of the CD28-B7 T-cell costimulatory pathway prevents later development and evolution of chronic renal allograft rejection. Our results indicate that T-cell recognition of alloantigen is a central event in initiating the process of chronic rejection, and that strategies targeted at blocking T-cell costimulation may prove to be a valuable clinical approach to preventing development of the process.
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PMID:Blockade of T-cell costimulation prevents development of experimental chronic renal allograft rejection. 890 33

Blocking CD28-B7 T-cell costimulation by CTLA4Ig induces tolerance to rat renal allografts and inhibits Th1, but spares Th2, cytokines. We now report on the mechanisms of CD28-B7 blockade in this model. Lymphocytes from CTLA4Ig-treated animals showed significant reduction of mixed lymphocyte response, as well as antidonor cytotoxic T-cell effector function, as compared with rejecting controls. Flow cytometry studies on sera of renal allograft recipients showed complete inhibition of antidonor humoral responses by CTLA4Ig. Analysis by reverse transcriptase-polymerase chain reaction and immunohistology showed that intragraft macrophage products, monocyte chemoattractant protein-1 and inducible nitric oxide synthase, were reduced by CTLA4Ig therapy. Immunohistologic studies also showed reduced intragraft macrophage infiltration and decreased staining for the fibrogenic and mitogenic growth factor, transforming growth factor-beta. These results indicate that CD28-B7 blockade inhibits cell-mediated and humoral immune responses, and suggest that strategies targeting T-cell costimulation may provide a novel approach to prevent chronic allograft rejection.
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PMID:CD28-B7 T cell costimulatory blockade by CTLA4Ig in the rat renal allograft model: inhibition of cell-mediated and humoral immune responses in vivo. 899 Mar 93

Retrovirally encoded proteases are responsible for the maturation of immature viral particles yielding mature, infectious virus. This is done by apparent (auto)-processing and self-activation of the protease (PR) from a larger viral gag-PR-(pol) protein (zymogen) precursor and subsequent processing of the viral reverse transcriptase (RT) and integrase (IN), and the gag protein precursor into mature gag proteins. Only the matured components are capable of forming capsids for intact, infectious viruses. Blocking this proteolytic process results in production of immature, non-infective virions. All retroviral proteases are aspartic-type proteases. Determination of the three-dimensional structure revealed retroviral proteases as small, nearly symmetric homodimers. This prompted de novo design of inhibitors for the HIV protease taking advantage of the unique symmetric structure of the active center, unparalleled by cellular proteases. The novel substances inhibit in vitro the HIV protease at nanomolar/subnanomolar concentrations and exhibit very low toxicity. They are inactive against human proteases such as renin or pepsin. The HIV protease inhibitors (PI) represent a promising alternative to the reverse transcriptase (RT) inhibitors (AZT, ddC, ddI) hitherto used with limited success for HIV chemotherapy. Clinical studies confirmed the low toxicity but revealed a pharmacological pattern typical for these hydrophobic compounds, such as low water solubility, poor oral bioavailibility, and short plasma half-life. Typical for antimicrobial agents, also a resistance phenomenon became evident. Latest clinical results show, however, promisingly that both problems might be overcome by application of the PI in combination with RT inhibitors (such as AZT, ddI or ddC) exerting a remarkable synergistic antiviral effect with lasting restoration of the CD4-T-cell level.
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PMID:Retroviral proteases: structure, function and inhibition from a non-anticipated viral enzyme to the target of a most promising HIV therapy. 899 87

Dystroglycans (DGs) bind laminin matrix proteins in skeletal and cardiac muscle and are expressed in other nonmuscle tissues. However, their expression in airway epithelial cells has not been demonstrated. We examined expression of DGs in the human airway epithelial cell line 1HAEo(-), and in human primary airway epithelial cells. Expression of the common gene for alpha- and beta-DG was demonstrated by reverse transcriptase/ polymerase chain reaction in 1HAEo(-) cells. Protein expression of beta-DG was demonstrated by both Western blot and flow cytometry in cultured cells. Localization of alpha-DG, using both a monoclonal antibody and the alpha-DG binding lectin wheat-germ agglutinin (WGA), was to the cell membrane and nucleus. We then examined the function of DGs in modulating wound repair over laminin matrix. Blocking alpha-DG binding to laminin in 1HAEo(-) monolayers using either glycosyaminoglycans or WGA attenuated cell migration and spreading after mechanical injury. alpha-DG was not expressed in epithelial cells at the wound edge immediately after wound creation, but localized to the cell membrane in these cells within 12 h of injury. These data demonstrate the presence of DGs in airway epithelium. alpha-DG is dynamically expressed and serves as a lectin to bind laminin during airway epithelial cell repair.
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PMID:Airway epithelial cell wound repair mediated by alpha-dystroglycan. 1115 52

Retrovirus minus strand strong stop transfer (minus strand transfer) requires reverse transcriptase-associated RNase H, R sequence homology, and viral nucleocapsid protein. The minus strand transfer mechanism in human immunodeficiency virus-1 was examined in vitro with purified protein and substrates. Blocking donor RNA 5'-end cleavage inhibited transfers when template homology was 19 nucleotides (nt) or less. Cleavage of the donor 5'-end occurred prior to formation of transfer products. This suggests that when template homology is short, transfer occurs through a primer terminus switch-initiated mechanism, which requires cleavage of the donor 5' terminus. On templates with 26-nt and longer homology, transfer occurred before cleavage of the donor 5' terminus. Transfer was unaffected when donor 5'-end cleavages were blocked but was reduced when internal cleavages within the donor were restricted. Based on the overall data, we conclude that in human immunodeficiency virus-1, which contains a 97-nt R sequence, minus strand transfer occurs through an acceptor invasion-initiated mechanism. Transfer is initiated at internal regions of the homologous R sequence without requiring cleavage at the donor 5'-end. The acceptor invades at gaps created by reverse transcriptase-RNase H in the donor-cDNA hybrid. The fragmented donor is eventually strand-displaced by the acceptor, completing the transfer.
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PMID:Mechanism of minus strand strong stop transfer in HIV-1 reverse transcription. 1249 70

The expression of IL-1beta and inducible nitric oxide synthase (iNOS) from iNOS hypo (GB2, B(6)B(6)) and hyper (K-strain, B(15)B(15)) responder chickens was examined. Compared to GB2, macrophages from K-strain expressed higher iNOS mRNA as quantitated by reverse transcriptase polymerase (RT-PCR) chain reaction after stimulation with 1 microgram/ml of Escherichia coli (E. coli) lipopolysaccharide (LPS). On the contrary, IL-1beta mRNA expression was comparable between K and GB2 macrophages at 3h post-LPS stimulation but persisted up to 9h only in GB2 macrophages. The LPS-inducible interleukin-1 (IL-1) surface receptor expression, measured by flow cytometry, was higher in GB2 than on K-strain macrophages. Blocking of IL-1 receptor by the anti-IL-1 receptor antibody reduced the LPS-mediated iNOS expression by 50% as quantified by competitive RT-PCR. Furthermore, iNOS activity (nitrite) was also reduced to 50%. However, this magnitude of inhibition was similar in both K and GB2 macrophages. While these observations suggest that IL-1beta is involved in mediating LPS-induced iNOS expression and activity, the differential response of GB1 and K-strain macrophages in terms of LPS-induced iNOS expression and activity is unlikely to be modulated by IL-1beta.
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PMID:Interleukin-1beta does not contribute to genetic strain-based differences in iNOS expression and activity in chicken macrophages. 1254 27

We evaluated the effects of rat anti-mouse IL-17 neutralizing monoclonal antibody (mAb) on the development of dextran sulfate sodium (DSS)-induced colitis. Tissue samples were evaluated by standard immunohistochemical procedure. The mucosal mRNA expression of cytokines was analyzed by reverse transcriptase-polymerase chain reaction (RT-PCR). In the mice treated with the anti-IL-17 mAb, the body weight was significantly lower, and anal prolapse and colon shortening were apparent. A histological analysis indicated that the anti-IL-17 mAb markedly enhanced the severity of colitis. The mucosal infiltration of CD4-positive helper T cells and CD11b-positive granulocytes-monocytes was increased in the anti-IL-17 mAb-treated mice. Treatment with the anti-IL-17 mAb increased the mucosal expression of mRNAs of tumor necrosis factor (TNF)-alpha, interferon (IFN)-gamma, IL-6, RANTES, and IP-10. Blocking of IL-17 activity in vivo using the anti-IL-17 mAb enhanced the development of DSS-colitis in mice. This suggests an inhibitory role for IL-17 in the development of DSS-colitis.
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PMID:Neutralization of interleukin-17 aggravates dextran sulfate sodium-induced colitis in mice. 1496 96


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