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

Treatment of the human immunodeficiency virus (HIV) is restricted by therapeutic escape. The biological mechanisms of this chemoresistance rely notably on the modulation of cell kinase and P-glycoprotein (P-gp) expression. In this study, we investigated, in cynomolgus macaques, the roles of SHIV89.6P infection and of HAART in the mRNA expression of these cell factors. SHIV infection, or associated pathophysiological disorders, increase both thymidine kinase and thymidylate kinase mRNA expression and decrease those of P-gp. On the other hand, the expression of other cell kinases is not modulated. In parallel, HAART accentuates the decrease of P-gp expression and attenuates the increase of kinase expression. On the whole, such metabolic disorders, evidenced herein an animal model of HIV infection, could be involved in HIV-infected patients.
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PMID:[Evaluation of the effect of early and massive tritherapy on the expression of cellular factors potentially implicated in antiretroviral therapy resistance]. 1094 47

Cellular cytoplasmatic thymidine kinase 1 (TK1) catalyzes the intracellular phosphorylation of anti-HIV-1 nucleoside analogs zidovudine (AZT) and stavudine (d4T) to the corresponding monophosphate form. In HIV-1-infected patients, treated with combination therapy including one of these compounds for more than 1 year, enzymatic activity of TK1 in peripheral blood mononuclear cells (PBMC) was determined by radioactive assay. TK1 activity in PBMC of HIV-1-infected patients correlated with CD4 cell count (r = 0.4, p<0.05) and HIV-1 RNA copy number (r = 0.4, p<0.05), being lower in patients with decreased CD4 cell count and high viral load. Furthermore,TK1 activity differs between HIV-1-infected individuals treated for more than 6 months (13.5 pmol/mg/h) compared to patients treated for less than 6 months (28.1 pmol/mg/h; p<0.05) with chemotherapeutic agents including thymidine analogs. The results demonstrate that TK1 deficiency in PBMC of HIV-1 infected patients may develop due to continuous treatment with thymidine analogs and correlates with a more progressed stage of disease expressed as diminished CD4 cell count and increased viral load.
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PMID:Activity of cellular thymidine kinase 1 in PBMC of HIV-1-infected patients: novel therapy marker. 1096 25

Our understanding of the pathogenesis of acyclovir (ACV)-resistant herpes simplex virus (HSV) is limited, especially with regard to reactivation and recurrent disease. To further explore the pathogenesis of ACV-resistant HSV-2 viruses, we used the guinea pig model of genital HSV-2 infection to evaluate several ACV-resistant isolates of both thymidine kinase (Tk)-altered and Tk-deficient phenotypes obtained from HIV-infected patients. Two plaque-purified workpools from each isolate were initially evaluated. Each produced acute disease and at least one clinical recurrence. The two strains that produced the most severe primary disease and most recurrences, one Tk-deficient virus and one Tk-altered virus, were further evaluated and shown to produce acute and recurrent genital disease similar to that seen with wild-type viruses. Furthermore, the reactivated virus producing recurrent lesions could be a pure population with minimal Tk activity. Finally, we showed that topical foscarnet treatment could alter disease and vaginal virus replication following vaginal inoculation with these two ACV-resistant strains. Using the guinea pig model of genital HSV-2 infection, we found that recurrent disease following infection with markedly Tk-deficient viruses was more common than expected, especially in select isolates. Furthermore, this model should be useful in evaluating potential new therapies for ACV-resistant HSV strains.
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PMID:Pathogenesis of acyclovir-resistant herpes simplex type 2 isolates in animal models of genital herpes: models for antiviral evaluations. 1097 68

We exploited the ability of lentiviral vectors to govern the stable transduction of cells irrespective of their cycling status to induce the reversible immortalization of human primary cells. First, bicistronic HIV-derived lentiviral vectors expressing GFP- and the HSV1 thymidine kinase and containing the LoxP sequence in their LTR (HLox) were used to transduce HeLa cells. Cre expression led to efficient proviral deletion, and unexcised cells could be eliminated by ganciclovir treatment. A human liver biopsy was then exposed to a combination of HLox vectors that harbored either the SV40 large T (TAg) or the human telomerase (hTERT) DNAs in place of GFP. This led to the isolation of liver sinusoidal endothelial cell (LSEC) clones that exhibited an immortalized phenotype while retaining most of the features of primary hLSEC. Complete growth arrest of these cells was observed in 2 days of Cre expression, and the resulting stationary culture could be kept for at least 2 weeks. Transduction of human adult pancreatic islets with HLox vectors coding for Tag and Bmi-1 also induced the proliferation of insulin-positive cells. These results indicate that lentivectors can be used to mediate the reversible immortalization of primary nondividing cells and should allow for the production of large supplies of a wide variety of human cells for both therapeutic and research purposes.
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PMID:Reversible immortalization of human primary cells by lentivector-mediated transfer of specific genes. 1102 Mar 57

The synthesis and biological activities of phosphotriester derivatives of 3'-azido-2',3'-dideoxythymidine (AZT) bearing a phenyl group or L-tyrosinyl residues are reported. The target compounds were obtained via either P(V) or 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. Furthermore, compounds incorporating an amino- and/or acid-substituted tyrosinyl residue demonstrated significant anti-HIV effects in thymidine kinase-deficient (TK(-)) cells showing their ability to act as mononucleotide prodrugs. The proposed decomposition process of these mixed mononucleoside aryl phosphotriesters may involve esterase activation followed by phosphodiesterase hydrolysis.
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PMID:S-Acyl-2-thioethyl aryl phosphotriester derivatives as mononucleotide prodrugs. 1108 82

Long-term treatment of HIV-1 infected patients with antiretroviral agents may result in failure of therapy due to the emergence of resistant virus mutants with decreased susceptibility to the therapeutic agents. Several authors have asked whether cellular factors, other than viral mutation may contribute to the declining efficiency of chemotherapy including nucleoside analogues and protease inhibitors (PI). Prolonged treatment with AZT may induce a defect of thymidine kinase activity in vitro and in vivo. Long-term treatment with other nucleoside analogues, such as d4T and 3TC, is also able to induce in host cells, a decreased sensitivity to the antiviral activity of these compounds. It is suggested that antiviral activity of PI could be modified by the expression of a protein P-gp that has been demonstrated to be able to bind PI and is involved in extrusion of anticancer agents.
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PMID:Cellular factors involved in the induction of resistance of HIV to antiretroviral agents. 1109 Oct 62

A human immunodeficiency virus type 1 (HIV-1)-based retroviral vector pseudotyped with HIV envelope containing the herpes simplex virus-thymidine kinase (HSV-TK) gene under the control of the HIV LTR promoter (pHXTKN) was constructed and stably transferred into human CD4(+) H9, CEM, and U937 cells. RNase protection assays did not initially detect expression of the HSV-TK gene in HXTKN-transduced CD4(+) cells (HXTKN/CD4), but expression was then efficiently induced by infection with HIV-1. MTT assays showed that after HIV-1 infection, the susceptibility of HXTKN/CD4 cells to ganciclovir (GCV) was 1000-fold higher than prior to infection. This enabled HIV-1-infected cells to be selectively killed by transduction with HXTKN followed by exposure to GCV. Because the HSV-TK gene is specifically transferred into HIV-1-permissive cells and expressed only after HIV-1 infection, the frequency of unwanted cell death should be low. Elimination of the HIV-1-infected cells effectively inhibited further spread of infectious virus. In addition, the integrated HIV vector sequences were repackaged on infection with HIV-1 and transferred to surrounding untransduced cells. These results are indicative of the potential benefits of using HIV vectors in gene therapies for the treatment of HIV-1 infection.
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PMID:Selective killing of human immunodeficiency virus-infected cells by targeted gene transfer and inducible gene expression using a recombinant human immunodeficiency virus vector. 1117 60

A group of unnatural 1-(2-deoxy-beta-D-ribofuranosyl)-2,4-difluorobenzenes having a variety of C-5 two-carbon substituents [-C...C-X, X = I, Br; -C...CH; (E)-CH=CH-X, X = I, Br; -CH=CH2; -CH2CH3; -CH(N3) CH2Br], designed as nucleoside mimics, were synthesized for evaluation as anticancer and antiviral agents. The 5-substituted (E)-CH=CH-I and -CH2CH3 compounds exhibited negligible cytotoxicity in a MTT assay (CC50 = 10(-3) to 10(-4)M range), relative to thymidine (CC50 = 10(-3) to 10(-5)M range), against a variety of cancer cell lines. In contrast, the C-5 substituted -C...C-I and -CH(N3)CH2Br compounds were more cytotoxic (CC50 = 10(-5) to 10(-6)M range). The -C...C-I and -CH2CH3 compounds exhibited similar cytotoxicity against non-transfected (KBALB, 143B) and HSV-1 TK+ gene transfected (KBALB-STK, 143B-LTK) cancer cell lines expressing the herpes simplex virus type 1 (HSV-1) thymidine kinase gene (TK+). This observation indicates that expression of the viral TK enzyme did not provide a gene therapeutic effect. The parent group of 5-substituted compounds, that were evaluated using a wide variety of antiviral assay systems [HSV-1, HSV-2, varicella-zoster virus (VZV), vaccinia virus, vesicular stomatitis, cytomegalovirus (CMV), and human immunodeficiency (HIV-1, HIV-2) viruses], showed that this class of unnatural C-aryl nucleoside mimics are inactive and/or weakly active antiviral agents.
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PMID:Synthesis of 1-(2-deoxy-beta-D-ribofuranosyl)-2,4-difluoro-5-substituted-benzenes: "thymine replacement" analogs of thymidine for evaluation as anticancer and antiviral agents. 1130 62

Copolymers of N-polyvinylpyrrolidone-acrylic acid (AB-1) and adamantane derivatives are known to possess marked antiviral activity in in vitro and in ovo models. Among the constructed preparations of AB-1 modified by adamantane derivatives some, especially AB-4 (modified by deitiforin), were found to show more extended antiviral activity and to inhibit markedly virus reproduction in susceptible permissive cell cultures and chicken embryos. In AB-4 treated cells and allantoic sacs, virus titers (influenza virus, herpes virus, and HIV) and virus antigen concentration were decreased. On the other hand, herpes virus-specific thymidine kinase and of DNA-polymerases isolated from Escherichia coli, Plectonema boryanum, and herpes virus type 1 infected murine brain tissue retained their activity after incubation with AB-4 or AB-2. The compounds investigated, in view of their effect on virus reproduction, are thought to be prospective as antiviral agents.
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PMID:Therapeutical effect of modified adamantane copolymer compounds: study of molecular mechanisms. 1144 Jan 76

At the Third International Conference on AIDS, Taipei, Taiwan, gene therapy, HIV quasi species, and Asian epidemiology were the main issues. Various effectors for gene therapy such as ribozyme, thymidine kinase and PKR were tested. Though not clinically available in the near future, gene therapy will likely play an important role in the combat against HIV. That non-syncytia-inducing HIV-1s are capable of direct T lymphocyte killing was reported and provides a possible explanation for progression to AIDS in patients in whom no syncytia-inducing HIV-1 could be found. Epidemiological data concerning Asia were presented in this meeting; among them is a detailed description of the current status of HIV infections in Taiwan. The HIV epidemic is still in its early stage in Taiwan, but some ominous signs favoring disease spread have been found. Copyright 1995 S. Karger AG, Basel
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PMID:AIDS in Asia: 3rd Taipei AIDS Meeting. 1172 36


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