UMLS:C0019693 - FACTA Search

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

We have previously reported that lymphoid and monocytic CD4+ cells transfected with and expressing a herpes simplex virus thymidine kinase (HSV-TK) gene, under the transcriptional control of the HIV long terminal repeat, are protected from HIV spread in the presence of 10 microM acyclovir. Furthermore, the expression of HSV-TK was able to enhance the antiviral effect of AZT. We now investigate the ability of retroviral vectors containing the HSV-TK gene under the transcriptional control of HIV regulatory sequences to transduce target cells. Bone marrow cells or lymphocytes might be genetically modified by these vectors in an HIV gene therapy strategy. In this study, we describe high-titer retroviral producer clones expressing the HSV-TK gene from an HIV LTR. Lymphoid cells transduced with one of these retroviruses express HSV-TK at a relatively low basal level. When the same cells express the HIV regulatory protein Tat, they are 10-fold more sensitive to killing by ganciclovir. Thus, this vector has potential application for gene therapy of HIV infection.
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PMID:Efficient retroviral gene transfer of a Tat-regulated herpes simplex virus thymidine kinase gene for HIV gene therapy. 949 29

The synthesis, hydrolysis, and antiviral evaluation of novel, lipophilic cycloSal-d4TMP derivatives 3a-h of the anti-HIV dideoxynucleoside 2',3'-dideoxy-2',3'-didehydrothymidine (d4T, 1) are reported. This pro-nucleotide concept has been designed to deliver d4TMP (2) by selective chemical hydrolysis. All compounds 3a-h were synthesized using phosphorus(III) chemistry in good yields and in somewhat lower yields using phosphorus(V) chemistry starting from substituted salicyl alcohols 6a-h. The phosphotriesters 3 were obtained without stereochemical preference with respect to the configuration at the phosphorus center as 1:1 diastereomeric mixtures. However, a few of the triesters 3 could be separated into the diastereomers by means of semipreparative HPLC. In a 1-octanol/phosphate buffer mixture, all compounds 3 exhibited 9-100-fold higher lipophilicity as judged from their Pa values as compared to d4T (1). Furthermore, in hydrolysis studies 3 decomposed under mild aqueous basic conditions releasing solely d4TMP (2) and the diols 6 following the designed tandem reaction sequence. A correlation of the electronic properties introduced by the substituents and the half-lives of triesters 3 was observed. Thus, by varying the substituent, the half-lives of 3 could be adjusted over a wide range of compounds still delivering d4TMP (2) selectively. Phosphotriesters 3 exhibited considerable activity against HIV-1 and HIV-2 in wild-type human T-lymphocyte (CEM/O) cells as well as mutant thymidine kinase-deficient (CEM/TK-) cells. Surprisingly, we observed a 3-80-fold difference in antiviral activity between the two diastereomers. Our data clearly prove that the cycloSal-d4TMPs deliver exclusively the nucleotide d4TMP not only under simulated hydrolysis conditions but also under cellular conditions and thus fulfill the thymidine kinase-bypass premise. Therefore, the cycloSal-nucleotide concept is the first reported pro-nucleotide system that delivers the dideoxynucleotide by a pH-driven, chemically activated, tandem reaction without the requirement of an enzymatic contribution.
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PMID:cycloSal-2',3'-dideoxy-2',3'-didehydrothymidine monophosphate (cycloSal-d4TMP): synthesis and antiviral evaluation of a new d4TMP delivery system. 955 75

Symptomatic human herpes simplex virus type 1 (HSV-1) infections are rather benign in immunocompetent individuals. The primary clinical manifestations of HSV-2 infection, which is mainly transmitted sexually, are anogenital lesions. Genital herpes affects one third of the world's population, and possibly 80% of those infected with HIV. HSV infections are especially severe and even life-threatening in people with AIDS. Only 20% of herpes seropositive persons have symptomatic infection, with the remainder asymptomatic but able to shed the virus. HSV infections are usually treated with nucleoside analogs such as acyclovir (ACV), but HSV eventually becomes resistant to ACV due to the loss or mutation of the viral thymidine kinase (TK) or changes in viral DNA polymerase. Gramicidin has recently been identified as a potent nontoxic anti-HIV agent 3-5 times more active than nonoxynol-9. Findings are reported from an assessment of the effect of gramicidin upon the replication of HSV-1 and HSV-2. Human WI-38 fibroblasts were inoculated with either HSV type in the presence of serial dilutions of gramicidin, while reduction in viral yield was measured by ELISA. The 50% inhibitory dose (IC50) of gramicidin against 3 HSV-1 and 4 HSV-2 isolates was equal to 0.3 mcg/ml and was comparable to the efficacy of ACV. The IC50 of gramicidin required to protect WI-38 from the cytolytic effect of HSV was 10 mcg/ml at day 5 postinfection, indicating that gramicidin was less active than ACV. Gramicidin nonetheless suppressed the replication of ACV-resistant thymidine kinase and DNA polymerase HSV mutants at doses effective against ACV-sensitive strains. These results suggest that gramicidin could be used against STDs and to prevent sexually transmitted HIV and HSV infections.
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PMID:The effect of gramicidin, a topical contraceptive and antimicrobial agent with anti-HIV activity, against herpes simplex viruses type 1 and 2 in vitro. 967 88

Long-term treatment of HIV-1-infected patients with antiretroviral agents may result in failure of therapy, due to the rapid emergence of resistant virus mutants with decreased susceptibility to therapeutic agents. However, in addition to viral resistance other factors, i.e. cellular factors, may contribute to the waning efficiency of chemotherapy. It has been shown in vitro that continuous treatment of cell lines with nucleoside reverse transcriptase inhibitors, such as 3'-azido-2',3'-dideoxythymidine (zidovudine, AZT), may induce decreased activity of cellular thymidine kinase (TK). Measurements of TK activity in ex vivo stimulated peripheral blood mononuclear cells of HIV-1-infected patients who undergo AZT long-term monotherapy as well as combination therapy provide evidence that diminished cellular TK activity may develop. This leads to the assumption that due to long-term treatment with nucleoside analogs, altered drug metabolism in host cells may contribute to inefficient activation of chemotherapeutic agents in HIV-1 patients. Thus, intracellular subtherapeutic levels of the active compounds may develop. In this intracellular environment, selection of resistant virus populations may be promoted. Due to the expanding number of antiretroviral compounds and the requirement for lifelong treatment of HIV-1-infected persons with antiretroviral agents, both viral and cellular resistance mechanisms must be considered in the context of failing chemotherapy.
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PMID:Viral and cellular factors for resistance against antiretroviral agents. 967 44

Nucleosides and nucleoside analogs are anabolised to their triphosphates by intracellular kinases. The anti-HIV analogue zidovudine (AZT) is phosphorylated by cytosolic thymidine kinase 1 (TK1), thymidylate kinase (dTMPK), and nucleoside diphosphate kinase. It is known that dTMPK is one of the rate-limiting steps in the activation of zidovudine. The activities of TK1, dTMPK, and deoxycytidine kinase (dCK) were determined in extracts of in vitro activated peripheral blood mononuclear cells from HIV-infected patients and healthy noninfected individuals. dTMPK activity was 10-fold lower and TK1 activity was five-fold lower in extracts from infected as compared to uninfected persons. Deoxycytidine kinase activities in the extracts from both groups were very similar. Differences in in vitro activation, as determined by flow cytometry, of the peripheral lymphocytes were not responsible for the decreased TK1 and dTMPK activities. A reduced level of intracellular azido-dideoxythymidinetriphosphate in activated mononuclear cells from HIV-infected patients was also observed. The low levels of TK1 and dTMPK in lymphocytes from HIV-infected patients may be related to the anergy phenomenon observed as a result of HIV infection. This effect should also be considered in the development of new anti-HIV drugs.
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PMID:Decrease in thymidylate kinase activity in peripheral blood mononuclear cells from HIV-infected individuals. 974 77

Epstein-Barr virus (EBV) has been known to be associated with many malignant tumors, including nasopharyngeal carcinoma (NPC). Previous studies have indicated that an EBV-encoded oncoprotein, latent membrane protein 1 (LMP1), is expressed in many NPC tissues. LMP1 has been shown to stimulate HIV LTR through the two NF-kappa B binding sites within this promoter. In this study, we examined the feasibility of using this property of LMP1 as a therapeutic strategy for the treatment of NPC. This therapy consists of the preferential killing of the LMP1-expressing cells by gene transfer using the NF-kappa B-mediated herpes simplex virus thymidine kinase (HSVtk)/ganciclovir (GCV) system. The 800-bp HIV-LTR, which contains two NF-kappa B binding sites, was used to drive the HSVtk gene. Stable C33A cell clones expressing the LMP1 and the HSVtk genes were subjected to the GCV sensitivity test. Results showed that cells expressing both the LMP1 and the HSVtk genes were highly sensitive to GCV treatment. These cells were introduced into nude mice subcutaneously and tumors became palpable within 2 weeks. GCV was then introduced intraperitoneally to these mice and the sizes of the tumors were measured daily. Results showed that the tumors regressed in the group of mice carrying cells that stably expressed both the LMP1 and the HSVtk genes, but not in mice carrying cells containing LMP1 or HSVtk alone. Our data indicate that the HSVtk gene expressed from a NF-kappa B-binding motif-containing promoter that is regulated by LMP1 may be used as an in vivo gene therapy strategy of EBV LMP1-expressing cancers such as NPC.
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PMID:Transcriptional activation of NF-kappa B activity by Epstein-Barr virus (EBV) LMP1 as a selective therapeutic strategy for EBV-associated diseases. 981 61

The purpose of the present study was to compare the decomposition pathways in CEM cell extracts of various phenyl phosphoramidate derivatives of AZT. In addition, the structures of their metabolites were identified. Correlations with their anti-HIV activities in a thymidine kinase deficient (TK-) CEM cell line have been established with a rationale of designing phosphoramidate pronucleotides capable of delivering intracellularly their respective 5'-nucleoside monophosphate derivatives.
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PMID:Anti-HIV pronucleotides: decomposition pathways and correlation with biological activities. 987 5

d4T-5'-[p-Bromophenyl methoxyalaninyl phosphate] (d4T-pBPMAP), a novel phenyl phosphate derivative of 2',3'-didehydro-2',3'-dideoxythymidine (d4T) that has an enhanced ability to undergo hydrolysis due to the electron withdrawing properties of its single bromo substituent at the para-position of the phenyl moiety, was found to yield substantially more of the key metabolite alaninyl d4T monophosphate (A-d4T-MP) than the unsubstituted d4T-5'-phenyl methoxyalaninyl phosphate or para-methoxy substituted d4T-5'-phenyl methoxyalaninyl phosphate. d4T-pBPMAP was tested for its anti-HIV-1 activity in peripheral blood mononuclear cells (PBMNC) and thymidine kinase (TK)-deficient CEM T-cells. d4T-pBPMAP was 12.6-fold more potent than the parent compound d4T in inhibiting p24 production (IC50 values: 44 nM vs 556 nM) and 41.3-fold more potent than d4T in inhibiting the reverse transcriptase (RT) activity (IC50 values: 57 nM vs 2355 nM) in HIV-1-infected TK-deficient CEM cells. Similarly, d4T-pBPMAP was more potent than the unsubstituted or para-methoxy substituted phenyl methoxyalaninyl phosphate derivatives of d4T. d4T-pBPMAP did not exhibit any detectable cytotoxicity to PBMNC or CEM cells at concentrations as high as 10,000 nM. Notably, d4T-pBPMAP was capable of inhibiting the replication of a zidovudine (ZDV/AZT)-resistant HIV-1 strain as well as HIV-2 in PBMNC at nanomolar concentrations. To our knowledge, this is the first demonstration that the potency of the d4T-aryl-phosphate derivatives can be substantially enhanced by introducing a single para-bromo substituent in the aryl moiety.
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PMID:Enhancing effects of a mono-bromo substitution at the para position of the phenyl moiety on the metabolism and anti-HIV activity of d4T-phenyl methoxyalaninyl phosphate derivatives. 987 88

The possibility of protecting human CD4+ lymphocytes from human immunodeficiency virus type 1 (HIV1) infection, through a suicide mechanism elicited by the HIV1 transcription apparatus itself, offers a potentially useful approach for gene therapy of the acquired immunodeficiency syndrome. A replication-defective lentiviral HIV1 vector (HYIRES-TK) was designed to carry both the hygromycin (Hy) phosphotransferase gene for positive selection and the thymidine kinase (TK) gene of herpes simplex virus driven by the viral long terminal repeat (LTR). The internal ribosome entry site (IRES) from encephalomyocarditis virus was placed between the two genes for their efficient simultaneous translation. Transient expression of active TK into transfected COS-1 cells was shown to be induced by Tat and Rev over a detectable basal level. By providing the missing viral proteins in trans, recombinant viruses were generated and used to transduce Jurkat cells. The Hy-resistant population of cells was sensitive to ganciclovir (GCV) and acyclovir (ACV), a result consistent with a basal level of TK expression. Cocultivation of transduced cells with cells chronically infected with HIV in the presence of 10 microM ACV, a concentration non-toxic for the uninfected cells, resulted in increased killing of cells transduced with the HY-IRES-TK vector. These data indicate that two genes can be expressed from the viral LTR in the context of an HIV1 vector, with the aid of an IRES sequence. The expression is inducible by the HIV proteins Tat and Rev and it is possible to specifically kill infected cells with subtoxic concentrations of drug. To decrease the sensitivity of the transduced cells towards GCV, a variant vector expressing a truncated TK was constructed. The truncated version was expressed at levels similar to those of wild-type TK but induced sensitivity towards GCV in transduced cells that was intermediate between that of untransduced cells and of cells expressing wild-type TK.
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PMID:Inducible expression of herpes simplex virus thymidine kinase from a bicistronic HIV1 vector. 992 18

New substituted-aryl phosphoramidate derivatives of the anti-HIV drug d4T were synthesized as membrane-soluble intracellular prodrugs for the free bioactive phosphate to establish relationship(s) between compound structure and in vitro antiviral activity. The majority of compounds demonstrated an elevation of in vitro potency relative to that of the parent nucleoside, and unlike d4T, all retained full activity in thymidine kinase-deficient cells. The compound bearing a p-chloro aryl group (8e) expressed nanomolar activity in vitro, a 14-fold increase in activity relative to that of the unsubstituted phosphoramidate (100-fold compared to d4T). An assay using pig liver esterase was used to establish the stability of the compounds to enzymatic degradation. While there was no apparent correlation between in vitro activity and half-life of enzymatic degradation, there was a close correlation between compound lipophilicity, determined by octanol/water partition coefficient, and in vitro potency. We suggest that substitutions made to the aryl moiety of the aryl phosphoramidate of d4T that result in enhancing lipophilicity may serve to increase the cellular uptake of the prodrug by passive diffusion, leading to the expression of antiviral potency at reduced prodrug concentrations.
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PMID:The presence of substituents on the aryl moiety of the aryl phosphoramidate derivative of d4T enhances anti-HIV efficacy in cell culture: A structure-activity relationship. 998 9

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