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Query: UMLS:C0019693 (HIV)
 170,526 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Suicide gene therapy using herpes simplex virus type-1 (HSV-1) thymidine kinase (TK) is a widely exploited approach for gene therapy of cancer and other hyperproliferative disorders. Despite its popularity, clinical success has been so far hampered mostly by the relative inefficiency of TK gene transfer and its limited bystander effect. Here we report that fusion of TK to an 11-amino-acid peptide from the basic domain of the HIV-1 Tat protein (Tat11) imparts cell membrane translocating ability to the enzyme and significantly increases its cytotoxic efficacy. In cells expressing Tat11-TK, this protein is found extracellularly, associated with cell surface heparan sulfate proteoglycans, and is released into the cell culture medium. Based on its interaction with HSPGs, the protein is then internalized by neighboring, nonexpressing cells, which become susceptible to cell death when treated with the nucleoside analogue acyclovir. As a consequence, co-cultures of wild-type cells with cells expressing Tat11-TK show increased sensitivity to ACV through a mechanism involving apoptosis. Modification of TK by fusion with Tat11 might constitute an important step for the optimization of TK suicide gene strategy for gene therapy of cellular proliferation.
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PMID:Transcellular transfer of active HSV-1 thymidine kinase mediated by an 11-amino-acid peptide from HIV-1 Tat. 1248 30

The synthesis, antiviral activity, and stability study of phosphotriester derivatives of 3'-azido-2',3'-dideoxythymidine (AZT) bearing modified l-tyrosinyl residues are reported. These compounds were obtained via phosphoramidite (P(III)) chemistry from the appropriate aryl precursors. All the derivatives were evaluated for their in vitro anti-HIV activity, and they appeared to be potent inhibitors of HIV-1 replication in various cell culture experiments, with EC(50) values between the micro- and nanomolar range, especially in thymidine kinase deficient (TK(-)) cells, showing their ability to act as mononucleotide prodrugs. The proposed decomposition process of these mixed mononucleoside aryl phosphotriesters successively involves an esterase and a phosphodiesterase hydrolysis.
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PMID:S-acyl-2-thioethyl aryl phosphotriester derivatives of AZT: synthesis, antiviral activity, and stability study. 1259 58

To test the concept that a replication-competent retrovirus carrying a suicide gene could have potential utility in the control of the natural virus infection in mammalian species, we constructed derivatives of a feline leukemia virus (FeLV) that is commonly associated with leukemia-lymphomas in this species. The FeLV, Rickard strain, subgroup A (FRA) genome contained at the 3' end of the envgene, an insert of an internal ribosomal entry site (IRES) linked to cDNA sequence of either herpes simplex virus thymidine kinase (HSV-TK) or a truncated HSV-TK (HSV-ATK) or yeast cytosine deaminase (CD). These constructs were transfected into feline fibroblast cells (H927). The viruses produced were determined to be replication-competent. The stable propagation of the full-length transgene was, however, dependent on the size of the insert, IRES-CD being the smallest in size (1031 bp) exhibiting maximal stability for at least up to six months. The protein products of the transgenes could be detected, despite the appearance of deleted proviruses at late passages. The transduced cells were susceptible to cytotoxic killing when the appropriate prodrug, ganciclovir (GCV), acyclovir (ACV) or 5-fluorocytosine (5-FC) was added to the culture medium. H927 cells, infected with another subgroup of FeLV, namely, FeLV-B or FeLV-C, could be superinfected by the FRA-suicide gene viruses and thus, subjected to killing. Interestingly, at an early stage of infection by the parental FRA, H927 cells could also be reinfected by the same subgroup FRA constructs to induce the suicide effect. Among the three constructs, the vector with the CD gene was determined to be superior to others in terms of stability, therapeutic index and bystander effect in the cell culture test system. While the in vivo correlates of the therapeutic effect in the feline model remain to be determined, our results do encourage investigation of the same concept in the control of HTLV and, perhaps even, HIV infection in humans.
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PMID:A potential therapeutic strategy to combat leukemia virus infection. 1267 28

The human T-lymphoid cell line H9 resistant to 3'-azido-2',3'-dideoxythymidine (AZT) has a very low level of thymidine kinase (TK) expression which accounts for the failure of AZT to inhibit HIV-1 replication. In the present study DNA methylation and histone deacetylation as possible mechanisms of decreased TK gene expression in the resistant cells were investigated. The resistant cells expressed high levels of DNA methyltransferases (DNMTs) 3a and 3b. The DNA methylation inhibitor, 5-aza-cytidine (5-aza-C), increased TK gene expression and antiviral activity of AZT in the resistant cells, while histone deacetylase inhibitor trichostatin A (TSA) had no effect. The results suggest that hypermethylation of the TK gene but not histone deacetylation in AZT-resistant H9 cells accounts for decreased TK gene expression and failure of AZT to inhibit HIV-1 replication probably due to overexpression of DNMT 3a and 3b.
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PMID:The mechanism of 3'-azido-2',3'-dideoxythymidine resistance to human lymphoid cells. 1273 16

A variety of substituted 5'-N-phthaloyl-3'-azido-2',3'-dideoxythymidine derivatives has been evaluated for their activity against HIV-1, HIV-2 and Moloney murine sarcoma virus (MSV) in cell culture. Most of the 3'-azido-2',3'-dideoxythymidine (AZT, zidovudine) derivatives showed antiviral activity in the lower micromolar concentration range and there was a close correlation between their anti-HIV and anti-MSV activity (r = 0.99). The adamantyl phthaloyl derivative was active at submicromolar concentrations. None of the compounds showed marked cytostatic activity. They did not inhibit recombinant HIV-1 reverse transcriptase. All compounds were inactive against HIV in thymidine kinase-deficient cells, pointing to the compounds' requirement to release free AZT to afford antiviral efficacy.
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PMID:Synthesis and antiviral activity of some 5'-N-phthaloyl-3'-azido-2',3'-dideoxythymidine analogues. 1452 30

The synthesis and in vitro anti-HIV activity of phosphoramidate diester derivatives of 3'-azido-2',3'-dideoxythymidine (AZT) bearing one S-pivaloyl-2-thioethyl (tBuSATE) group and various amino residues are reported. These compounds were obtained from an H-phosphonate strategy using an amidative oxidation step. Most of these derivatives appeared to inhibit HIV-1 replication, with EC(50) values at micromolar concentration in thymidine kinase-deficient (TK-) cells, revealing a less restrictive intracellular decomposition process than previously reported for other phosphoramidate prodrugs. The proposed decomposition pathway of this new series of mixed pronucleotides may successively involve an esterase and a phosphoramidase hydrolysis.
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PMID:S-acyl-2-thioethyl phosphoramidate diester derivatives as mononucleotide prodrugs. 1452 18

Synthesis and biological activities of several phosphotriester derivatives of 3'-azido-2',3'-dideoxythymidine (AZT) bearing a S-pivaloyl-2-thioethyl (tBuSATE) group and aryl residues derived from L-tyrosine are reported. All compounds showed marked anti-HIV activity in thymidine kinase-deficient CEM cells demonstrating their ability to deliver intracellularly the parent 5'-mononucleotide.
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PMID:SATE (aryl) phosphotriester series. I. Synthesis and biological evaluation. 1456 7

Cutaneous T cell lymphomas (CTCLs) are lymphoproliferative disorders involving the skin. Malignant cells have a CD4+ T-helper phenotype and are found in early stages of the disease in plaques and cutaneous tumors. MLV/HIV-pseudotyped retroviral vectors target gene transfer to CD4-positive T cells and are therefore well suited to be specific delivery vehicles to treat CTCLs. We established a mouse xenograft model for CTCL and generated MLV/HIV-pseudotyped vectors encoding the herpes simplex virus thymidine kinase (HSV-TK), a well-known suicide gene, to prove the efficacy of MLV/HIV vectors in CTCL treatment. Vector particles were intratumorally injected into CTCL nude mouse xenografts. Mice were systemically treated with ganciclovir (GCV) and the tumor tissue was analyzed. A significant delay in tumor growth was observed for HSV-TK-transduced and GCV-treated tumors. GFP expression could be detected exclusively in CD4+ cells of tumors after transduction with GFP-encoding control vectors. The data demonstrate a cell-specific in vivo gene delivery via MLV/HIV-pseudotyped vectors and open new avenues for the treatment of CTCL in humans.
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PMID:MLV/HIV-pseudotyped vectors: a new treatment option for cutaneous T cell lymphomas. 1459 8

Based on an improved multi-population genetic algorithm, a new fast flexible docking program, GAsDock, was developed. The docking accuracy, screening efficiency, and docking speed of GAsDock were evaluated by the docking results of thymidine kinase (TK) and HIV-1 reverse transcriptase (RT) enzyme with 10 available inhibitors of each protein and 990 randomly selected ligands. Nine of the ten known inhibitors of TK were accurately docked into the protein active site, the root-mean-square deviation (RMSD) values between the docking and X-ray crystal structures are less than 1.7A; binding poses (conformation and orientation) of 9 of the 10 known inhibitors of RT were reproduced by GAsDock with RMSD values less than 2.0A. The docking time is approximately in proportion to the number of rotatable bonds of ligands; GAsDock can finish a docking simulation within 60s for a ligand with no more than 20 rotatable bonds. Results indicate that GAsDock is an accurate and remarkably faster docking program in comparison with other docking programs, which is applausive in the application of virtual screening.
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PMID:GAsDock: a new approach for rapid flexible docking based on an improved multi-population genetic algorithm. 1532 86

Starting from commercially available (rac)-3-cyclohexene-1-carboxylic acid, a series of purine and pyrimidine cis-substituted cyclohexenyl and cyclohexanyl nucleosides were synthesized through a key Mitsunobu reaction. Antiviral evaluations were performed on HIV, coxsackie B3, and herpes viruses (HSV-1, HSV-2, VZV, HCMV). Three compounds showed moderate activity against HSV-1 and coxsackie viruses. Specific computer modeling studies were performed on HSV-1 thymidine kinase in order to understand the enzyme activation of an analogue showing moderate antiviral activity.
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PMID:Synthesis and antiviral evaluation of cis-substituted cyclohexenyl and cyclohexanyl nucleosides. 1565 58


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