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)

Herpes simplex virus type 1 (HSV-1) infection induces expression of the human immunodeficiency virus type 1 (HIV-1) provirus in the chronically infected T-cell line ACH-2. The HSV-1-mediated induction correlates with the appearance of two NF-kappa B-specific proteins of 55 and 85 kDa in the nucleus and with the binding of 50-kDa nuclear protein to the LBP-1 binding site of the untranslated leader sequence of the HIV-1 long terminal repeat. The HSV-1-induced LBP-1 binding protein, designated HLP-1, is present exclusively in HSV-1-infected, but not in phorbol-12-myristate-13-acetate- or tumor necrosis factor alpha-treated ACH-2 cells. Both the NF-kappa B and LBP-1 target sequences, when inserted either alone or together 5' of a heterologous minimal promoter (thymidine kinase), confer inducibility by HSV-1 infection in a transient transfection assay. Thus, it appears that the HSV-1-mediated activation of HIV-1 provirus is brought about by the binding of both NF-kappa B and HLP-1 specific proteins to two distinct regions of HIV-1 long terminal repeat.
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PMID:Herpes simplex virus type 1-mediated induction of human immunodeficiency virus type 1 provirus correlates with binding of nuclear proteins to the NF-kappa B enhancer and leader sequence. 131 71

We have stably expressed in CD4+ lymphoid cells the herpes simplex virus type 1 thymidine kinase (HSV1-TK) gene under the control of the human immunodeficiency virus (HIV) promoter and transactivation response element sequences. Upon HIV infection these regulatory sequences were transactivated, switching on high-level expression of HSV1-TK. This in turn caused the death of HIV-infected cells when they were cultured in the presence of acyclovir, a nucleoside analog that becomes toxic after phosphorylation by HSV1-TK. The elimination of HIV-infected cells resulted in the arrest of HIV spreading in the culture. Complete protection of HSV1-TK-expressing cells was obtained using acyclovir concentrations that are commonly detected in the plasma of patients treated for HSV1 infection. Thus, expression of this DNA construct generates a pool of CD4+ booby-trapped cells that, as a population, are resistant to HIV infection. Our data provide a rationale for the use of suicide genes in the design of gene therapy of HIV infection.
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PMID:Selective killing of CD4+ cells harboring a human immunodeficiency virus-inducible suicide gene prevents viral spread in an infected cell population. 134 66

2',3'-Dideoxyuridine (ddU) is ineffective at controlling human immunodeficiency virus type 1 (HIV-1) infection in human T cells, because it is not biotransformed to the active 5'-triphosphate. The metabolic block resides in the poor substrate affinity of ddU for cellular nucleoside kinases. This problem cannot be overcome by supplying the preformed nucleotides, because such compounds are unable to penetrate cells. To circumvent the requirement of ddU for enzymic phosphorylation, we have prepared bis(pivaloyloxymethyl) 2',3'-dideoxyuridine 5'-monophosphate (piv2 ddUMP), as a potential membrane-permeable prodrug of ddUMP, and investigated its metabolism and anti-HIV activity in two human T cell lines, one with wild-type thymidine kinase activity (MT-4) and the other deficient in thymidine kinase activity (CEM-tk-). The 5'-mono-, di-, and triphosphates of ddU were formed in both cell lines after exposure to piv2-ddUMP. In contrast, phosphorylated metabolites were not observed in cells treated with ddU or ddUMP alone. piv2-ddUMP also reduced the cytopathic effects of HIV-1 in MT-4 cells (ED50, 4.75 microM) and inhibited virus production in culture fluid (ED50, 20 microM). In addition, piv2-ddUMP protected CEM-tk- cells from HIV-1 infection, as demonstrated by inhibition of intracellular p24 antigen levels (ED50, 3 microM) and reverse transcriptase activity in culture medium (Ed50, 2.5 microM). Based on these findings, we propose that the "masked nucleotide" strategy may make available for development nucleoside analogues hitherto considered inactive because of failure to undergo biotransformation to the corresponding 5'-monophosphates. Moreover, by circumventing metabolic dependency on nucleoside kinases, the strategy may overcome acquired resistance to nucleoside analogues caused by the loss or depletion of nucleoside kinases.
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PMID:Membrane-permeable dideoxyuridine 5'-monophosphate analogue inhibits human immunodeficiency virus infection. 137 82

Toward gene therapy for the treatment of human immunodeficiency virus type 1 (HIV-1) infections in AIDS, Moloney murine leukemia virus-derived retroviral vectors were engineered to allow constitutive and tat-inducible expression of an HIV-1 5' leader sequence-specific ribozyme (Rz1). These vectors were used to infect the human CD4+ lymphocyte-derived MT4 cell line. The stable MT4 transformants expressing an HIV-1 RNA-specific ribozyme, under the control of the herpes simplex virus thymidine kinase (tk) promoter, were found to be somewhat resistant to HIV-1 infection as virus production was delayed. In cells allowing ribozyme expression under control of the simian virus 40 or cytomegalovirus promoter, the rate of HIV-1 multiplication was slightly decreased, and virus production was delayed by about 14 days. The highest level of resistance to HIV-1 infection was observed in MT4 cells transformed with a vector containing a fusion tk-TAR (trans activation-responsive) promoter to allow ribozyme expression in a constitutive and tat-inducible manner; no HIV-1 production was observed 22 days after infection of these cells. These results indicate that retroviral vectors expressing HIV-1 RNA-specific ribozymes can be used to confer resistance to HIV-1 infection.
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PMID:Resistance to human immunodeficiency virus type 1 (HIV-1) infection in human CD4+ lymphocyte-derived cell lines conferred by using retroviral vectors expressing an HIV-1 RNA-specific ribozyme. 189 2

The inhibitory effects of a series of antiviral compounds on human immunodeficiency virus type 1 (HIV-1) were evaluated in a plaque assay (PA) in MT-4 cells and a focal immunoassay (FIA) in CD4+ HeLa cells. Similar 50% inhibitory concentrations (IC50) were obtained for the sulfated polysaccharides when measured by PA or FIA: the IC50 values of dextran sulfate and pentosan polysulfate were 0.8 microgram/ml and 0.35 microgram/ml, respectively. Also, comparable IC50 values (ranging from 1.42 to 2.71 microM) were obtained for purine 2',3'-dideoxyribosides (i.e. DDA, DDI and DDG) when evaluated by PA or FIA. In contrast, the IC50 values of pyrimidine 2',3'-dideoxyribosides were invariably 4- to 10-fold lower when monitored by PA than FIA: the IC50s of AZT, D4T and DDC in the PA were 0.015, 0.094 and 0.038 microM, respectively, and in the FIA were 0.062 microM, 0.29 microM and 0.46 microM, respectively. The differential anti-HIV-1 activities found with AZT, D4T and DDC in the PA and FIA systems may at least be related in part to differences in the metabolism of the compounds (i.e. phosphorylation by thymidine kinase or 2'-deoxycytidine kinase) between MT-4 and CD4+ HeLa cells. The novel anti-HIV-1 compounds tetrahydro-imidazo[4,5,1-jk][1,4]-benzodiazepin-2(1H)-thione (TIBO) derivatives, R82150 and R82913, and the acyclouridine derivative 1-[(2-hydroxyethoxy)methyl]-6-phenylthiothymine (HEPT) were also more inhibitory to HIV-1 in the PA than FIA system. The IC50 values of R82150, R82913 and HEPT, as based on PA, were 0.005, 0.003 and 0.79 microM, respectively. Their IC50 values, as based on FIA, were 0.020 microM, 0.015 microM and 3.77 microM, respectively. The TIBO derivatives emerged as the most effective HIV-1 inhibitors of the compounds tested whether assayed by PA or FIA.
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PMID:Anti-HIV-1 activity of antiviral compounds, as quantitated by a focal immunoassay in CD4+ HeLa cells and a plaque assay in MT-4 cells. 198 Jan 26

Oxygen-sulfur exchange at the C-4 carbonyl of several modified pyrimidine nucleosides, including 3'-azido-3'-deoxythymidine (AZT), is described in an effort to enhance the lipophilicity and, thereby, the delivery to the central nervous system of the sulfur analogues without compromising the anti-HIV activities of the parental structures. Preparation of 3'-azido-3'-deoxy-4-thiothymidine (3) proceeded from 4-thiothymidine (1) and utilized the same methodology developed for the initial synthesis of AZT. Thiation of 2',3'-didehydro-3'-deoxythymidine (4a) and 2',3'-didehydro-2',3'-dideoxyuridine (4c) was carried out with Lawesson's reagent on the corresponding 5'-O-benzoate esters, 4b and 4d, to give 5a and 5c, respectively. The latter, on alkaline hydrolysis, gave 2',3'-didehydro-3'-deoxy-4-thiothymidine (5b) and 2',3'-didehydro-2',3'-dideoxyuridine (5d), respectively. The same series of reactions were applied to the 5'-O-benzoate esters of 2',3'-dideoxyuridine (6a) and 3'-deoxythymidine (6b) to give 2',3'-dideoxy-4-thiouridine (7d) and 3'-deoxy-4-thiothymidine (7b), respectively. Characterization of the saturated and unsaturated thionucleosides included mass spectrometric studies. Under electron impact conditions, the thiated analogues gave more intense parent ions than the corresponding oxygen precursors. The lipophilicity of thymidine and the 3'-deoxythymidine derivatives are enhanced significantly, as indicated, by increases in corresponding P values (1-octanol-0.1 M sodium phosphate) upon replacement of the 4-carbonyl oxygens by sulfur. Compounds 5b, 5d, 7b, and 7d were evaluated for their effects on HIV-induced cytopathogenicity of MT-2 and CEM cells. Only 5b and 7b were moderately active in protecting both cell lines against the cytolytic effect of HIV. The inhibitory effects of analogues 5b, 5d, 7b, and 7d on thymidine phosphorylation by rabbit thymus thymidine kinase were evaluated. Only 3 showed moderate affinity (Ki = 54 microM) for the enzyme. The generally weak anti-HIV activities of the remaining thio analogues are consistent with correspondingly low susceptibilities to thymidine kinase phosphorylation as estimated from the respective Ki values of the synthetic nucleosides. However, the phosphorylation of the 5'-monophosphate derivatives to their respective 5'-triphosphates must also be considered in connection with the weak in vitro anti-HIV effects of these thiated compounds.
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PMID:Synthesis and in vitro evaluation of some modified 4-thiopyrimidine nucleosides for prevention or reversal of AIDS-associated neurological disorders. 215 6

Transcription of human immunodeficiency virus type 1 (HIV-1) is regulated by cis-acting DNA elements located in the viral long terminal repeats, by viral transregulatory proteins, and by cellular transcription factors acting in concert to modulate the degree of viral expression. We demonstrate that a DNA fragment corresponding to the central portion of the HIV-1 genome exhibits enhancer activity when cloned upstream of the thymidine kinase promoter of herpes simplex virus. This enhancer is inducible by phorbol 12-myristate 13-acetate in HeLa cells and is independent of its position and orientation with respect to the promoter. We have mapped the activity of the enhancer to two independent domains encompassing nucleotides 4079-4342 (end of the pol gene) and nucleotides 4781-6026 (vif gene and first coding exon of tat). This intragenic enhancer and its subdomains demonstrate cellular specificity because they are only active in specific cell lines. The presence of similar intragenic enhancer elements in other retroviruses suggests that they might be a conserved feature of this family of viruses.
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PMID:Identification and characterization of an enhancer in the coding region of the genome of human immunodeficiency virus type 1. 235 55

The crystal structure of 3'-azido-3'-deoxy-thymidine (AZT), an antiviral agent that inhibits HIV reverse transcriptase, has been determined from three-dimensional x-ray diffractometer data. The crystal structure contains two independent molecules of AZT forming a hydrogen bonded dimer but exhibiting different conformations. These conformations are different from those theoretically calculated by molecular mechanics methods. The azido groups associate with each other and interrupt the base stacking, forming a sandwich of two stacked bases. The close conformational similarity of AZT to thymidine explains why AZT is a good substrate for thymidine kinase. The selective inhibition of reverse transcriptase by AZT is not due to any conformational restrictions imposed by the azido group but likely due to their stereoelectronic properties.
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PMID:Conformation and sandwiching of bases by azido groups in the crystal structure of 3'-azido-3'-deoxy-thymidine (AZT), an antiviral agent that inhibits HIV reverse transcriptase. 245 15

HIV is the causative agent of AIDS. The purpose of this study was to examine the biochemical pharmacology of the anti-viral agent zidovudine (AZT) in the T-cell origin line (CEM). We have shown that zidovudine is activated by thymidine kinase (TK) in CEM cells to the triphosphate anabolite, which is incorporated into DNA. One microM zidovudine is sufficient for saturation of activation by TK and also of zidovudine monophosphate, by thymidylate kinase, to the diphosphate. Zidovudine triphosphate peaked 4 h after initiation of drug administration in CEM cells and then declined biexponentially. Nucleoside triphosphate (NTP) cellular concentrations declined rapidly in the cells after exposure to zidovudine. Concomitantly phosphorylation of zidovudine to zidovudine monophosphate and zidovudine monophosphate to zidovudine diphosphate declined in a similar manner in the CEM cells. The amount of zidovudine anabolite incorporated into purified DNA peaked 1 h after zidovudine treatment and declined thereafter with first order elimination kinetics. These studies elucidate the cellular activation of zidovudine in a T-cell line, CEM, and enhance our understanding of this important anti-HIV drug.
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PMID:Biochemical pharmacology of zidovudine in human T-lymphoblastoid cells (CEM). 250 44

Infections caused by herpes simplex virus (HSV) are a significant source of morbidity in immunocompromised patients. Acyclovir is often used prophylactically and therapeutically in patients with human immunodeficiency virus infection. The emergence of acyclovir-resistant strains of HSV capable of causing disease has been recognized. We report a case in which a thymidine kinase-deficient mutant of HSV caused extensive disease in a patient with AIDS. This case emphasizes that virus recovered from nonhealing lesions should be submitted for further study, which may advance our understanding of the interaction between host defense and drug-resistant strains.
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PMID:Mucocutaneous dissemination of acyclovir-resistant herpes simplex virus in a patient with AIDS. 254 44


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