Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0019693 (HIV)
 170,526 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The synthesis of some new aminoadamantane derivatives is described. The new compounds were evaluated against a wide range of viruses [influenza A H1N1, influenza A H2N2, influenza A H3N2, influenza B, parainfluenza 3, herpes simplex virus type 1 (HSV-1) and type 2 (HSV-2), thymidine kinase-deficient (TK-) HSV-1, vaccinia, vesicular stomatitis, polio 1, Coxsackie B4, Sindbis, Semliki forest, Reo 1, varicella-zoster virus (VZV), TK- VZV, human cytomegalovirus (HCMV), and human immunodeficiency virus type 1 (HIV-1) and type 2 (HIV-2)]. Some of them proved markedly active against the influenza A H2N2 (compounds 4a,b, 5a, 6a, and 7a), H3N2 (compounds 5a, 6a, and 7a), and H1N1 (compounds 4b,c and 6d). Since compounds 5a, 6a, and 7a, amantadine, and rimantadine showed the same comparative pattern of potency against influenza strains H2N2, H3N2, and B, it may postulated that they act according to a similar mechanism, with regard to their "amine" effect, on the M2 ion channel of influenza A (H1N1, H2N2, or H3N2). In general, no significant activity was noted with any of the new compounds against any of the other viruses tested, making their activity against influenza virus more specific and striking. Borderline activity was noted with some of the compounds (4b,c, 5a-c, and 8a) against HIV-1.
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PMID:Synthesis and antiviral activity evaluation of some new aminoadamantane derivatives. 2. 876 14

The recent discovery of long term AIDS nonprogressors who harbor nef-attenuated HIV suggests that a naturally occurring live vaccine for AIDS may already exist. Animal models have shown that a live vaccine for AIDS, attenuated in nef, is the best candidate vaccine. There are considerable risks, real and perceived, with the use of live HIV vaccines. We have introduced a conditional lethal genetic element into HIV-1 and simian immunodeficiency virus (SIV) molecular clones deleted in nef. The antiviral strategy we employed targets both virus replication and the survival of the infected cell. The suicide gene, herpes simplex virus thymidine kinase (tk), was expressed and maintained in HIV over long periods of time. Herpes simplex virus tk confers sensitivity to the antiviral activity of acyclic nucleosides such as ganciclovir (GCV). HIV-tk and SIV-tk replication were sensitive to GCV at subtoxic concentrations, and virus-infected cells were eliminated from tumor cell lines as well as primary cell cultures. We found the HIV-tk virus to be remarkably stable even after being cultured in media containing a low concentration of GCV and then challenged with the higher dose and that while GCV resistant escape mutants did arise, a significant fraction of the virus remained sensitive to GCV.
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PMID:A candidate live inactivatable attenuated vaccine for AIDS. 879 Apr 13

The expression of the gene encoding herpes simplex virus thymidine kinase (HSV-TK) in eukaryotic cells confers sensitivity to antiherpetic drugs such as acyclovir and ganciclovir. This property has been proposed for use in gene therapy approaches to kill either cancer cells or HIV-infected cells. Several animal experiments have shown the regression of tumors after in vivo transfer of the HSV-TK gene followed by ganciclovir treatment. Furthermore, CD4+ T cells harboring the HSV-TK gene under the control of HIV regulatory sequences are protected from HIV spreading in the presence of acyclovir. Thus, the HSV-TK gene has potential applications in gene therapy for the treatment of cancer and HIV infection.
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PMID:Gene therapy against cancer and HIV infection using the gene encoding herpes simplex virus thymidine kinase. 879 90

The purpose of this study was to investigate the mechanism of acquired cellular resistance to AZT, a mechanism that has been described as a potential source of drug resistance in addition to viral mutations. To study this phenomenon the kinetics parameters of thymidine kinase (TK) activity have been defined in CEMazt, a cell line previously selected for resistance to AZT, in comparison with the parental AZT-sensitive CEM cells. The results revealed that the value of the maximum velocity (Vmax) of TK activity for deoxythymidine (dThd) phosphorylation is decreased in CEMazt as compared to the wild-type cell line (Vmax: CEM = 105.3 +/- 17.6 nmol/hr/mg of protein; CEMazt = 0.3 +/- 0.02 nmol/hr/mg of protein; p < 0.001). Furthermore, the enzyme affinity versus dThd is lower in CEMazt as compared to CEM (Km: CEM = 0.9 +/- 0.2 microM; CEMazt = 1.6 +/- 0.2 microM; p < 0.01). Consequently phosphorylation efficiency, expressed as the ratio between Vmax and Km, is also reduced in CEMazt (p < 0.001). To evaluate whether such a phenomenon may also occur in patients, ex vivo experiments were carried out by using PBMCs from HIV-infected patients, treated or not treated with AZT. The results (mean values from 10 patients for each group) indicate that a prolonged treatment (> 6 months) with AZT may modify the enzymatic kinetics of TK, leading to a significant reduction in the phosphorylation efficiency of the enzyme (4.07 +/- 1.7 in treated patients versus 13.5 +/- 1.7 in untreated patients; p < 0.001). These results indicate that AZT treatment can also induce a defect in TK activity in patients.
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PMID:Long-term exposure to zidovudine affects in vitro and in vivo the efficiency of phosphorylation of thymidine kinase. 883

The ability to direct expression of genes to astrocytes in mice has been one of the major motivators of transcriptional analyses of the glial fibrillary acidic protein (GFAP) gene. Another has been the possibility of discovering signaling pathways that operate during development, disease, and injury-all states that increase GFAP gene activity-by identifying and working back from the responsible DNA elements. Here we review studies in both these areas and provide practical guidelines for the construction and analysis of GFAP transgenes. Analyses of the GFAP promoter from cell transfection experiments are summarized to provide background information for the studies in transgenics. Another section provides practical information on the construction and analysis of transgenic mice, with particular reference to GFAP transgenes. The survey of analyses of GFAP transcription elements in transgenic mice reveals that a segment of about 2 kb of the 5'-flanking region of the gene is sufficient to direct reporter gene activity to astrocytes with high specificity. This segment also supports a response to brain injury by upregulation of the activity. Developmentally, the transgene activity is seen by e12.5, several days earlier than GFAP protein or mRNA has been detected. GFAP transcription control regions have already been used to express several proteins in astrocytes to evaluate their biological effects. These proteins include IL-3, IL-6, TGF-beta1, the HIV envelop protein gp120, the MHC Class I Db protein, somatosatin, CNTF, and the herpes simplex virus thymidine kinase. In the future many other GFAP transgenes are expected to be produced, with increasing knowledge of the GFAP regulatory elements promising greater sophistication through promoters that can be regulated, have higher activity, and target activity to particular brain regions.
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PMID:GFAP Transgenic Mice 895 47

A lymphoblastoid cell line, CEM, was rendered resistant to zidovudine (AZT) in vitro by exposure to low but gradually increasing concentrations of the drug. This type of cellular resistance seems to be due to a defect of thymidine kinase (TK) activity that is acquired by cells grown in the presence of AZT. In fact, enzymatic studies with extracts from AZT-resistant cells (CEMazt), have shown that the value of the maximum velocity (Vmax) of TK activity measured with AZT and for deoxythymidine (dThd) is decreased as compared to sensitive CEM cells. Furthermore, the enzyme affinity for AZT and dThd is reduced in CEMazt. Further experiments have shown that such cells do not show resistance to other nucleoside analogs, such as ddI, ddC, AraT and D4T, suggesting that the phosphorylation pathways different from those involving TK are unaltered. Ex vivo experiments performed by using peripheral blood mononuclear cells (PBMC) from HIV infected individuals revealed that a prolonged treatment with AZT may modify the affinity of TK for dThd, thus suggesting that the aforementioned phenomenon may occur also in vivo.
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PMID:Alteration of thymidine kinase activity in cells treated with an antiviral agent. 912 32

Serum selenium levels were determined cross-sectionally in 57 HIV-infected patients who were classified according to the Centers for Disease Control (CDC) 1993 classification system. Mean serum selenium levels were lower in CDC stage II (58.7 +/- 12.2 micrograms/L; p < 0.01; n = 18) and stage III (47.6 +/- 11.3 micrograms/L; p < 0.01; n = 19) HIV-infected patients, than in healthy subjects (80.6 +/- 9.6 micrograms/L; n = 48) and stage I patients (73.6 +/- 16.5 micrograms/L; n = 20). Serum selenium levels were positively correlated with CD4 count, CD4/8 ratio, hematocrit, and serum albumin (r = 0.42; r = 0.39; r = 0.48; and r = 0.45; p < 0.01, respectively) and inversely with serum levels of thymidine kinase (r = -0.49; p < 0.01; n = 49) and beta 2-microglobulin (r = -0.46; p < 0.001; n = 49). In addition, serum selenium levels in 20 randomly selected AIDS-free individuals (CDC I: n = 10; CDC II: n = 10) were inversely correlated with serum concentrations of interleukin-8 (IL-8) and soluble tumor necrosis factor receptors (sTNFR) types I and II. There was no correlation with serum immuneglobulin A and total serum protein levels. The results show that the progressive deprivation of serum selenium in HIV-infection is associated with loss of CD(4+)-cells and with increased levels of markers of disease progression and inflammatory response.
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PMID:Serum selenium versus lymphocyte subsets and markers of disease progression and inflammatory response in human immunodeficiency virus-1 infection. 915 10

Many antiviral drugs must be metabolized to their active form by cellular enzymes. Their antiviral activity may therefore be limited by an inefficient metabolism, leading to low intracellular concentration of the active form or to the accumulation of toxic intermediate metabolites. Gene transfer might be used to overcome such limitations by transducing a gene able to increase intracellular drug metabolism. To prove such a concept, we chose the well-studied paradigm of zidovudine (AZT) metabolism and anti-HIV activity. AZT-triphosphate is the active form of AZT, acting through inhibition of HIV reverse transcription. In human cells, the rate-limiting step for AZT phosphorylation is catalyzed by the thymidylate kinase. We thus tested the capacity of herpes simplex virus type 1 thymidine kinase, which possesses a thymidylate kinase activity, to improve AZT metabolism and antiviral activity. Our results show enhanced AZT phosphorylation in HSV-1 TK-expressing lymphoid and monoblastoid cells, which correlated with significantly improved antiviral activity against different strains of HIV-1. The antiviral activity of Foscarnet, another reverse transcriptase inhibitor that does not require phosphorylation, remained unchanged. These results suggest that gene transfer might be envisioned for genetic pharmacomodulation of antiviral drugs.
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PMID:Use of herpes simplex virus thymidine kinase to improve the antiviral activity of zidovudine. 928 20

T-lymphocytes transduced with the conditionally toxic herpesvirus thymidine kinase gene (HSV-1 TK) are increasingly becoming important tools in genetic therapy approaches for treating viral infections and cancers. Therefore, the effects of different antiviral nucleoside drugs on the growth inhibition of parental and HSV-1 TK-transduced human T-lymphocyte cell lines (H9 and CEM TK-) were examined. As expected, both transduced cell lines were most sensitive to growth inhibition by ganciclovir (GCV). While the presence of HSV-1 TK did not potentiate 3'-azido-2',3'-dideoxythymidine (AZT) growth inhibition of H9 cells containing cellular TK; transduction of HSV-1 TK into the cellular TK-deficient CEM cells (CEM TK-) restored sensitivity to AZT. In both transduced cell lines, an HSV-1 TK-dependent growth inhibition with 2',3'-didehydro-2',3'-dideoxythymidine (d4T) was observed and a Km of 143 microM for d4T and HSV-1 TK was determined. Metabolic labeling analysis showed that drug metabolism correlated with the observed effects on cell growth. The effects of HIV-1 replication in the CEM TK- cell lines in the presence of AZT or d4T was evaluated. CEM TK- cells are largely resistant to AZT or d4T inhibition of HIV-1 replication, however, transduction of HSV-1 TK into the CEM TK- cells completely restored AZT and d4T inhibition of HIV-1 replication. These studies confirm the requirement for a thymidine kinase activity for the anti-HIV activities of d4T and suggest that AZT, but not d4T, could be potentially administered to patients receiving HSV-1 TK-transduced lymphocytes.
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PMID:Metabolism and activities of 3'-azido-2',3'-dideoxythymidine and 2',3'-didehydro-2',3'-dideoxythymidine in herpesvirus thymidine kinase transduced T-lymphocytes. 929 57

S-TK (Serum thymidine kinase) levels were determined by means of a radioenzyme assay (REA). In 95% of healthy controls (n = 97), S-TK values were below 8.5 U/L. In patients with monoclonal gammopathies of undetermined significance (MGUS) (n = 27) or polyclonal gammopathies (n = 45) the cut off was 10.3 U/L respectively 25 U/L. Patients with viral disease (n = 16), especially infections with Epstein-Barr virus, Hepatitis-virus and HIV, had elevated S-TK values of up to 215 U/L. In 95 patients with multiple myeloma (MM) and 103 patients with other various non-Hodgkin lymphomas (NHL) S-TK levels were investigated. With regard to monoclonal gammopathies, MGUS had lower S-TK than MM patients (p < 0.05) and patients with stage I MM according to Durie and Salmon had S-TK levels significantly lower than those with more advanced stages (p < 0.01). There was a correlation between S-TK and plasma cell labeling index (r = 0.56, p < 0.001). Patients with chronic lymphocytic leukemia showed significantly higher S-TK levels in the RAI stages 3 and 4 than in stages 1 and 2 (p < 0.01). In cases of other malignant NHL in progression sensitivities of S-TK were found to be: immunocytoma 36%, centrocytic/centroblastic-centrocytic lymphoma 54% and high-grade NHL 40% (cut off defined on lymphomas in remission). S-TK levels varied in MM according to the course of disease and response to therapy decreasing at remission and increasing again at relapse. Analogous variations were found in the other NHL. After two years, 83% of patients with a pretreatment S-TK of < 10 U/L and 47% of the patients with a S-TK of > or = 10 U/L were still alive. S-TK proved to be a highly significant prognostic indicator for MM patients (log-rank and Wilcoxon: p < 0.0001). In the other NHL patients with a S-TK level greater than 10 U/L had a median follow-up of only 7 months. NHL patients with lower S-TK levels did not yet reach the median survival time (log-rank and Wilcoxon. p < 0.005). Our results suggest that the determination of S-TK may help to monitor the clinical course of NHL during therapy and predict the prognosis of NHL.
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PMID:Serum thymidine kinase in non-Hodgkin lymphomas with special regard to multiple myeloma. 932 92


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