UMLS:C0001175 - FACTA Search

Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Target Concepts:

Query: UMLS:C0001175 (AIDS)
120,706 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A heterogeneous herpes simplex virus type 2 (HSV-2) population was characterised from an AIDS patient with relapsing genital ulcer. The isolate had an unusual antiviral spectrum, showing resistance to penciclovir and susceptibility to acyclovir. Two viral populations were plaque purified, one resistant and the other susceptible to both antiviral drugs. The resistant clone was deficient in thymidine kinase (TK) activity and a nucleotide substitution, thymine for cytosine, at position 153 was identified in its TK gene. This mutation resulted in an amino acid change, arginine to tryptophan, in the ATP binding site. In the deficient mutant, a loss of virulence was observed in mice.
...
PMID:Characterisation of penciclovir resistant acyclovir sensitive herpes simplex virus type 2 isolated from an AIDS patient. 1504 49

It has been demonstrated that prolonged in vivo or in vitro treatment with some nucleosides analogs may favor the selection of cells with a reduced activity of enzymes involved in the phosphorylation of these drugs leading to a reduced sensitivity to their antiretroviral action. The aim of this study was to evaluate the effect, in vivo, of zidovudine and stavudine treatment on thymidine kinase (TK) activity. The results obtained showed that TK levels in PBMC from naive patients and stavudine-treated patients did not significantly differ (naive TK = 4.16 +/- 1.19 U/mg protein; stavudine TK = 3.65 +/- 1.73 U/mg protein; p = 0.42), suggesting that the treatment with this nucleoside analog is not associated to a defect of TK activity. On the contrary, PBMC from zidovudine-treated patients showed a significant reduction in TK activity compared to naive patients (naive TK = 4.16 +/- 1.19 U/mg protein; zidovudine TK = 2.70 +/- 1.54; p = 0.014. Although the clinical significance of these results has to be established, we can speculate that stavudine and zidovudine, which are presumably phosphorylated by the same cellular kinases, might display a different ability to in vivo select cells with a resistant phenotype.
AIDS Res Hum Retroviruses 2004 Jul
PMID:Lack of reduction of thymidine kinase activity in stavudine-treated HIV-infected patients. 1530 13

Over 20 years into the ever-worsening AIDS pandemic, genetic variation remains the greatest obstacle for treating and preventing HIV-1 infection. Mutation rate assays for HIV-1 have been reported; however, none measure directly the forward mutation rate during replication of the virus in cell culture while still retaining the ability to propagate and further study mutant proviruses. Therefore, the objective of the current study was to develop such a phenotypic cell-based assay for measuring the forward mutation rate of HIV-1. Conventional recombinant DNA techniques and polymerase chain reaction were used to create a replication defective HIV-1 vector, pNL4-3Delta+cass, which is based on the NL4-3 strain and contains the thymidine kinase gene from human herpes virus type 1 as the mutational target. A series of transfection and infection steps were used to introduce the vector into 143B cells, which are negative for thymidine kinase function, and produce vector virus for a single cycle of replication. Viral titers were measured by counting the number of drug resistant colonies on the assay plates, and forward mutation rates were calculated from the viral titers. Mutant proviruses were sequenced to determine the types of genetic alterations that occurred. The average forward mutation rate for HIV-1 was 2.2 x 10(-5)mutations/base/cycle. The majority of mutations were base substitutions, including high frequencies of C-->U and G-->A transitions. Single adenosine insertions were also observed frequently. The new assay is economical and provides a direct measurement of the mutation rate during a single cycle of viral replication. Target cells containing mutant proviruses survive the drug selection process and may be propagated for further analysis. The new assay is novel and has many advantages over previous mutation rate assays and thus will be very useful in future studies on genetic variation of HIV-1.
...
PMID:A new cell-based assay for measuring the forward mutation rate of HIV-1. 1566 56

Mitochondrial thymidine kinase or TK-2 belongs to the family of mammalian deoxynucleoside kinases (dNKs) that catalyze the phosphorylation of deoxynucleosides to their corresponding deoxynucleoside monophosphates by gamma-phosphoryl transfer of ATP. These enzymes are instrumental in the activation of deoxynucleoside analogues with biological and therapeutic properties. Moreover, dNKs are fundamental to maintain dNTPs pools for DNA synthesis and repair. TK-2 has a mitochondrial localization and is the only thymidine kinase that is physiologically active in non-proliferating and resting cells. Several recent investigations point to an important role of TK-2 in the maintenance of mitochondrial dNTPs pools. Indeed, mutations in the gene encoding TK-2 have been associated with mitochondrial DNA (mtDNA) depletion that mostly affects skeletal muscle. Moreover, TK-2 has been suggested to be implicated in mitochondrial toxicity associated to prolonged treatments with nucleoside analogues (i.e AZT for the treatment of AIDS patients). In this scenario, TK-2 inhibitors could be a useful tool to further clarify both the physiological role of TK-2 in the maintenance of mitochondrial dNTP pools, and the possible contribution of TK-2 to the mitochondrial toxicity of pyrimidine nucleoside analogues. In the present article we review the most recent literature covering different aspects of TK-2 as well as published TK-2 inhibitors, with special emphasis on acyclic nucleoside analogues that have been described by our research groups and whose prototype compound is 1-[(Z)-4-(triphenylmethoxy)-2-butenyl]thymine.
...
PMID:Mitochondrial thymidine kinase inhibitors. 1630 27

Establishment of selective antiviral chemotherapy has achieved dramatic improvement of the prognosis of several viral infections. It has been considered for a long time that, unlike bacterial infections, viral diseases cannot be successfully treated with chemotherapeutic agents, since viral replication mostly depends on the host-cellular machinery. In fact, some compounds were reported to inhibit viral replication even in the 1950s and 1960s, yet they were also quite toxic to the host cells. The first antiviral compound that strongly inhibits viral replication without affecting the uninfected cells is the anti-herpes agent acyclovir (ACV), which was discovered in the 1970s. Furthermore, in the 1980s, the world-wide epidemic of AIDS caused by human immunodeficiency virus type 1 (HIV-1) infection has dramatically accelerated the development of new antiviral agents. At present, most of the effective antivirals are targeted at virus-specific enzymes, such as ACV for herpes virus thymidine kinase, zidovudine for HIV-1 reverse transcriptase, squinavir for HIV-1 protease, and oseltamivir for neuraminidase of influenza virus. These agents can be administered systemically without serious side effects. However, several drawbacks, including delayed toxicity and drug-resistance, are associated with long-term treatment with several antiviral agents mostly in highly active antiretroviral therapy for HIV-1 infection. Thus, it seems still mandatory to continue the search for more effective and less toxic compounds against various viral infections.
...
PMID:[Advances in antiviral chemotherapy]. 1630 32

Nucleoside analogs were first approved by the U.S. Food and Drug Administration for use against HIV-AIDS in 1987. Since then, these agents, now commonly referred to as nucleoside reverse transcriptase inhibitors (NRTIs), have become essential components of the Highly Active Antiretroviral Therapy (HAART) drug combinations used for treatment of Human Immunodeficiency Virus-1 (HIV-1) infections. Their antiretroviral activity is likely two-fold: incorporation of the drug into viral DNA and inhibition of the viral reverse transcriptase. However, incorporation of the drug into host nuclear and mitochondrial DNA may be largely responsible for dose-limiting toxicities. Azidothymidine (AZT, 3'-azido-3'-deoxythymidine, zidovudine), the first NRTI approved for the therapy of HIV-1, is incorporated into DNA, causes mutations in the hypoxanthine-guanine phosphoribosyl-transferase (HPRT) and thymidine kinase (TK) genes, and induces micronuclei, chromosomal aberrations, sister chromatid exchange, shortened telomeres, and other genotoxic effects in cultured cells. Genomic instability would be predicted as a consequence of these events. Metabolic pathways that result in the phosphorylation of AZT play a crucial role in AZT-DNA incorporation, and may be altered after prolonged treatment. For example, thymidine kinase 1, the enzyme responsible for AZT mono-phosphorylation, is down-regulated during long-term exposure and appears to be associated with AZT-induced replication inhibition and the accumulation of cells in S-phase. Detailed information on the mechanisms underlying NRTI-associated antiretroviral efficacy, toxicity, and metabolic resistance were not available when AZT was first approved for use as an antiretroviral agent. Current insights, based on 15 years of research, may lead to intervention strategies to attenuate toxicity without altering drug efficacy.
...
PMID:Mechanisms of genotoxicity of nucleoside reverse transcriptase inhibitors. 1639 95

A human T-lymphoblastoid cell line that is resistant to the antiviral activity of zidovudine (ZDV) and moderately resistant to lamivudine (3TC) has been obtained as a result of prolonged treatment with a combination of three nucleoside analogues (NA), ZDV, 3TC, and abacavir (ABV). These cells, called CEM(ZLA), are fully sensitive to ABV. The cellular resistance of the CEM(ZLA) cells to ZDV correlates with significant reductions in thymidine kinase (TK) activity and in the amount of intracellular TK protein. Interestingly, the reduction in TK activity led to impairment of the ability of CEM(ZLA) to accumulate the triphosphate metabolite of ZDV. However, the moderately 3TC-resistant phenotype of CEM(ZLA) cannot be ascribed to a similar reduction in deoxycytidine kinase activity. Compared to the parental CEM cells, CEM(ZLA) cells express a high level of multidrug resistance protein 4 (MRP4), which could reduce the intracellular concentration of 3TC. This study shows that the exposure of cells to a combination of NAs is capable of simultaneously affecting more than one target site to confer resistance and that NAs display differing abilities to select cellular resistance mechanisms.
AIDS Res Hum Retroviruses 2006 Oct
PMID:The effects of prolonged treatment with zidovudine, lamivudine, and abacavir on a T-lymphoblastoid cell line. 1706 65

Mitochondrial toxicity limits nucleoside reverse transcriptase inhibitors (NRTIs) for acquired immune deficiency syndrome. NRTI triphosphates, the active moieties, inhibit human immunodeficiency virus reverse transcriptase and eukaryotic mitochondrial DNA polymerase pol-gamma. NRTI phosphorylation seems to correlate with mitochondrial toxicity, but experimental evidence is lacking. Transgenic mice (TGs) with cardiac overexpression of thymidine kinase isoforms (mitochondrial TK2 and cytoplasmic TK1) were used to study NRTI mitochondrial toxicity. Echocardiography and nuclear magnetic resonance imaging defined cardiac performance and structure. TK gene copy and enzyme activity, mitochondrial (mt) DNA and polypeptide abundance, succinate dehydrogenase and cytochrome oxidase histochemistry, and electron microscopy correlated with transgenesis, mitochondrial structure, and biogenesis. Antiretroviral combinations simulated therapy. Untreated hTK1 or TK2 TGs exhibited normal left ventricle mass. In TK2 TGs, cardiac TK2 gene copy doubled, activity increased 300-fold, and mtDNA abundance doubled. Abundance of the 17-kd subunit of complex I, succinate dehydrogenase histochemical activity, and cristae density increased. NRTIs increased left ventricle mass 20% in TK2 TGs. TK activity increased 3 logs in hTK1 TGs, but no cardiac phenotype resulted. NRTIs abrogated functional effects of transgenically increased TK2 activity but had no effect on TK2 mtDNA abundance. Thus, NRTI mitochondrial phosphorylation by TK2 is integral to clinical NRTI mitochondrial toxicity.
...
PMID:Targeted transgenic overexpression of mitochondrial thymidine kinase (TK2) alters mitochondrial DNA (mtDNA) and mitochondrial polypeptide abundance: transgenic TK2, mtDNA, and antiretrovirals. 1732 72

3'-Azido-3'-deoxythymidine (AZT), a nucleoside analogue used for the treatment of acquired immunodeficiency syndrome (AIDS), induced a significant dose-related increase in the thymidine kinase (Tk) mutant frequency (MF) in L5178Y/Tk(+/-) 3.7.2C mouse lymphoma cells. Treatment with 1 mg/ml (3,742 muM) AZT for 24 hr resulted in a MF of 407 x 10(-6) compared to a control MF of 84 x 10(-6). The MFs of the large and small colony mutants resulting from AZT exposure were 142 x 10(-6) and 265 x 10(-6), respectively. One hundred and fifty mutants from the 1 mg/ml (3,742 muM) AZT-treated culture and sixty-nine mutants from independent untreated cultures were isolated and analyzed. LOH analysis using a heteromorphic microsatellite locus located in the Tk gene was performed to determine the presence or absence of the Tk(+) allele. Eight other microsatellite markers spanning the entire mouse chromosome 11 also were examined for heterozygosity to determine the extent of LOH. In addition, Tk gene dosage analysis was conducted using Real-Time PCR in those mutants showing LOH at the Tk locus. The presence of only one Tk allele based on Real-Time PCR indicated that the mutant resulted from deletion while the presence of two alleles was consistent with a recombination event. More mutants from the AZT-treated culture showed Tk LOH than did independent mutants from the untreated cultures (91% vs. 64%) and the induced mutants also showed distinct chromosome 11 LOH patterns. The mutation spectrum of mutants from AZT-treated cells was also significantly different from that of spontaneous mutants. More deletions and fewer intragenic mutations were observed in the mutants from the AZT-treated culture than independent mutants from the untreated control. Our data indicate that AZT primarily induced LOH mutations in L5178Y mouse lymphoma cells and a large number of LOH mutations resulted from deletions.
...
PMID:3'-azido-3'-deoxythymidine induces deletions in L5178Y mouse lymphoma cells. 1735 34

The production, manipulation and rescue of a bacterial artificial chromosome clone of Vaccinia virus (VAC-BAC) in order to expedite construction of expression vectors and mutagenesis of the genome has been described (Domi & Moss, 2002, PNAS99 12415-20). The genomic BAC clone was 'rescued' back to infectious virus using a Fowlpox virus helper to supply transcriptional machinery. We apply here a similar approach to the attenuated strain Modified Vaccinia virus Ankara (MVA), now widely used as a safe non-replicating recombinant vaccine vector in mammals, including humans. Four apparently full-length, rescuable clones were obtained, which had indistinguishable immunogenicity in mice. One clone was shotgun sequenced and found to be identical to the parent. We employed GalK recombination-mediated genetic engineering (recombineering) of MVA-BAC to delete five selected viral genes. Deletion of C12L, A44L, A46R or B7R did not significantly affect CD8(+) T cell immunogenicity in BALB/c mice, but deletion of B15R enhanced specific CD8(+) T cell responses to one of two endogenous viral epitopes (from the E2 and F2 proteins), in accordance with published work (Staib et al., 2005, J. Gen. Virol.86, 1997-2006). In addition, we found a higher frequency of triple-positive IFN-gamma, TNF-alpha and IL-2 secreting E3-specific CD8+ T-cells 8 weeks after vaccination with MVA lacking B15R. Furthermore, a recombinant vaccine capable of inducing CD8(+) T cells against an epitope from Plasmodium berghei was created using GalK counterselection to insert an antigen expression cassette lacking a tandem marker gene into the traditional thymidine kinase locus of MVA-BAC. MVA continues to feature prominently in clinical trials of recombinant vaccines against diseases such as HIV-AIDS, malaria and tuberculosis. Here we demonstrate in proof-of-concept experiments that MVA-BAC recombineering is a viable route to more rapid and efficient generation of new candidate mutant and recombinant vaccines based on a clinically deployable viral vector.
...
PMID:Recombination-mediated genetic engineering of a bacterial artificial chromosome clone of modified vaccinia virus Ankara (MVA). 1828 94

<< Previous 1 2 3 4 5 6 7 8 9 Next >>