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

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Query: EC:2.7.7.49 (reverse transcriptase)
31,746 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Lamivudine is a dideoxynucleoside analogue which undergoes intracellular phosphorylation to the putative active metabolite, lamivudine triphosphate. Lamivudine triphosphate prevents HIV replication by competitively inhibiting viral reverse transcriptase. Lamivudine has a unique resistance profile and has the ability to delay resistance to zidovudine and restore zidovudine sensitivity in zidovudine-experienced patients. Combination antiretroviral drug therapy is now generally considered preferable to monotherapy as first-line treatment for patients with HIV infection. In double-blind trials in antiretroviral drug-experienced or -naive adults, improvements in surrogate markers of disease progression were significantly greater in patients receiving lamivudine plus zidovudine combination therapy than in patients who received either drug as monotherapy. Preliminary results of CAESAR, a large multicentre trial in patients with moderately advanced HIV infection receiving zidovudine-based treatment regimens, show a 54% reduction in the rate of disease progression or death with the addition of lamivudine, compared with the addition of placebo. Initial virological data from studies of combination regimens including lamivudine and protease inhibitors are also promising, although the longer term efficacy of these regimens remains to be established. Improvements in surrogate disease markers were also seen in children and adolescents with symptomatic HIV infection who received lamivudine monotherapy. Studies of lamivudine-containing combination therapy in children and adolescents are in progress, but few data have yet been published. Lamivudine is generally well tolerated as monotherapy or in combination with other antiretroviral agents in HIV-infected adults with CD4+ counts > or = 100 cells/microliter. Gastrointestinal disturbances were reported as the most common adverse events during lamivudine monotherapy or combination therapy. Lamivudine appears to be less well tolerated in patients with advanced disease (CD4+ cell counts < 100 cells/microliter), but more data are required to clarify its tolerability in such patients. Pancreatitis has been reported in children with advanced disease during treatment with the drug, but was not directly attributable to lamivudine therapy. Thus, lamivudine, administered in combination with zidovudine, is now established as an effective agent for the treatment of antiretroviral drug-experienced or -naive individuals with asymptomatic or symptomatic HIV disease. Moreover, encouraging preliminary data suggest that lamivudine is poised to become an important component of other regimens, in combination with drugs such as the protease inhibitors.
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PMID:Lamivudine. A review of its antiviral activity, pharmacokinetic properties and therapeutic efficacy in the management of HIV infection. 909 65

HIV-infected individuals, who received 3TC monotherapy over one year, generally had lower plasma viral burden than at base-line. This was in spite of high-level resistance to this compound and the appearance of the M184V substitution in the HIV reverse transcriptase (RT) gene, responsible for diminished sensitivity to 3TC. This apparent contradiction is explained by an increase in the fidelity of the HIV RT, conferred by the M184V mutation, on the basis of the following observations. First, titers of viral neutralizing antibodies, as measured against sequential autologous HIV isolates, remained stable in this population in contrast to rapid declines in patients treated with other drugs. This suggests that increased fidelity of M184V RT may limit variability in the HIV env gene and result in protracted effectiveness of anti-viral immune responsiveness. Second, recombinant HIV, that contained the M184V substitution in RT, could not replicate in the presence of d4T, AZT, Nevirapine, Delavirdine or Saquinavir, using previously described protocols for the generation of drug resistance in vitro.
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PMID:Increased fidelity of drug-selected M184V mutated HIV-1 reverse transcriptase as the basis for the effectiveness of 3TC in HIV clinical trials. 920 7

Several anti-HIV drugs acting on different steps of virus replication were tested in our experimental model of primary monocyte/macrophages; the results were compared with the activity found in lymphocytes. Nucleoside analogues (AZT, ddI, ddC, d4T, PMEA, 3TC etc.) show greater activity in macrophages (M/M) than in lymphocytes. In particular, the EC50 of AZT, ddC, and ddI in M/M is 2- to 100-fold lower than that found in lymphocytes. This greater efficacy of nucleoside analogues in M/M depends on the enhancement of their chain-terminating activity by the low levels of endogenous deoxynucleoside-triphosphates (dNTP) usually found in resting cells such as M/M. Non-nucleoside reverse transcriptase inhibitors (NNRTI) do not act as chain terminators (thus their antiviral effect is not related to the intracellular concentrations of dNTP); as a consequence the activity of TSAO, HEPT, TIBO, and other NNRTI tested in M/M is similar to that found in lymphocytes. Regarding inhibitors of binding and fusion of HIV, we found that their anti-HIV activity is markedly decreased (or even nullified) when M/M are treated with cytokine activators of M/M function and enhancers of HIV replication. More relevant from a clinical standpoint, protease inhibitors are able to inhibit HIV replication in chronically infected macrophages (i.e., cells carrying the proviral genome already integrated in the host genome). All other inhibitors of late stage of virus life cycle tested (antisense-rev, anti-tat, interferon-alpha and -gamma, phosphorothioate analogues, GLQ-223, etc.) were totally inactive in chronically infected macrophages. The different effects of various classes of HIV inhibitors in lymphocytes and macrophages suggests that AIDS therapy should consider all aspects of the pathogenesis of HIV infection and must be restricted to drugs, or combinations of drugs, active against both lymphocytes and M/M in all body compartments where the virus hides and replicates.
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PMID:Inhibition of replication of HIV in primary monocyte/macrophages by different antiviral drugs and comparative efficacy in lymphocytes. 922 5

Exposure of human immunodeficiency virus to the nucleoside analogue lamivudine (3TC) rapidly selects for resistant variants with a valine at codon 184 (M184V) in the catalytic site of reverse transcriptase. In vitro, 184V demonstrated increased enzyme fidelity and suppressed zidovudine resistance. Clinical trials demonstrated that 3TC-zidovudine combination therapy results in a strong and sustained antiviral response. To investigate the role of 184V on in vivo virus evolution, the effect of zidovudine addition in 3TC-pretreated patients harboring 184V was studied. In vivo, no significant change in fidelity was observed with 184V, shown by generation of the classical pattern of zidovudine mutations. Of interest, in contrast to zidovudine monotherapy, in which just one substitution is sufficient for in vivo development of significant zidovudine resistance, multiple substitutions are required for the same level of zidovudine resistance in strains harboring 184V. This need for multiple substitutions may be one of the mechanisms explaining the sustained antiretroviral response of the 3TC-zidovudine combination.
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PMID:Lamivudine-resistant human immunodeficiency virus type 1 variants (184V) require multiple amino acid changes to become co-resistant to zidovudine in vivo. 923 4

Two mutants of HIV-1 reverse transcriptase (RT) associated with high-level resistance of the virus to AZT (RT-AZT: D67N, K70R, T215Y, K219Q, and M41L) or 3-TC (RT-3TC: M184V) were expressed in Escherichia coli and purified. None of these mutants showed significant changes in the affinity and kinetics of binding to a DNA/DNA primer/template. RT-AZT was investigated in detail with respect to its kinetics of incorporation of nucleotides. No change in the relative rates of TMP and AZTMP incorporation could be detected for RT-AZT with respect to wild type RT. These results imply that there is no increased discrimination against AZTTP in the mutant. This was found for DNA/DNA and DNA/RNA primer/template. Additionally, rapid kinetics of incorporation of 3'-amino-3'-deoxythymidine 5'-monophosphate (a possible metabolite of AZT) were investigated and compared with TMP incorporation, but no difference in its relative rates of incorporation between wild type RT and RT-AZT was detected. In contrast, the already very slow rate of incorporation of 3-TCMP seen with wild type enzyme was drastically reduced (by a factor of 23 and 36 with DNA/DNA primer/template and DNA/RNA primer/template, respectively) for RT-3TC, showing a clear correlation between in vitro and in vivo effects. The affinity of 3-TCTP to the RT-3TC-primer/template complex was not affected by the mutation M184V. A 1.6-fold cross-resistance to ddATP, the converted form of the prodrug ddI, could also be shown for RT-3TC, but no cross-resistance to ddCTP was detected. Additionally, rapid kinetics of AZTMP incorporation by RT-3TC were investigated. There was an indication of a slightly higher rate of incorporation of AZTMP by RT-3TC than wild type RT.
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PMID:Single-step kinetics of HIV-1 reverse transcriptase mutants responsible for virus resistance to nucleoside inhibitors zidovudine and 3-TC. 925 28

Nelfinavir mesylate (formerly AG1343) is a potent and selective, nonpeptidic inhibitor of human immunodeficiency virus type 1 (HIV-1) protease that was discovered by protein structure-based design methodologies. We evaluated the antiviral and cytotoxic effects of two-drug combinations of nelfinavir with the clinically approved antiretroviral therapeutics zidovudine (ZDV), lamivudine (3TC), dideoxycytidine (ddC; zalcitabine), stavudine (d4T), didanosine (ddI), indinavir, saquinavir, and ritonavir and a three-drug combination of nelfinavir with ZDV and 3TC against an acute HIV-1 strain RF infection of CEM-SS cells in vitro. Quantitative assessment of drug interaction was evaluated by a universal response surface approach (W. R. Greco, G. Bravo, and J. C. Parsons, Pharm. Rev. 47:331-385, 1995) and by the method of M. N. Prichard and C. Shipman (Antiviral Res. 14:181-206, 1990). Both analytical methods yielded similar results and showed that the two-drug combinations of nelfinavir with the reverse transcriptase inhibitors ZDV, 3TC, ddI, d4T, and ddC and the three-drug combination with ZDV and 3TC resulted in additive to statistically significant synergistic interactions. In a similar manner, the combination of nelfinavir with the three protease inhibitors resulted in additive (ritonavir and saquinavir) to slightly antagonistic (indinavir) interactions. In all combinations, minimal cellular cytotoxicity was observed with any drug alone and in combination. These results suggest that administration of combinations of the appropriate doses of nelfinavir with other currently approved antiretroviral therapeutic agents in vivo may result in enhanced antiviral activity with no associated increase in cellular cytotoxicity.
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PMID:Activities of the human immunodeficiency virus type 1 (HIV-1) protease inhibitor nelfinavir mesylate in combination with reverse transcriptase and protease inhibitors against acute HIV-1 infection in vitro. 933 41

Stavudine (d4T) is a pyrimidine nucleoside analogue used in the treatment of human immunodeficiency virus (HIV) infection. It inhibits viral reverse transcriptase as do zidovudine (AZT), didanosine (ddI), zalcitabine (ddC) and lamivudine (3TC), which comprise the family of nucleoside HIV-reverse transcriptase inhibitors. Stavudine is currently approved by the US Food and Drug Administration for the treatment of patients who have become intolerant to or have failed to response to zidovudine, didanosine or zalcitabine therapy. Oral administration of stavudine results in maximal concentrations within 2 hours and increases linearly as doses increase. The absolute oral bioavailability is high, approaching 100%. There is evidence to suggest that stavudine does not accumulate in the plasma. It distributes into total body water and appears to enter cells by non-facilitated diffusion. Penetration into the cerebrospinal fluid occurs, as does the transfer of the drug across human placental tissue. Stavudine is cleared quickly by both renal and nonrenal processes. The pharmacokinetic properties of stavudine in children are similar to those of adults. The pharmacokinetic parameters of stavudine were not affected by simultaneous administration of didanosine. It appears that stavudine at doses < 2 mg/kg/day is most efficient at increasing CD4 + cell numbers. While stavudine is reported to be less cytotoxic than zidovudine, the principal toxicity in humans is peripheral neuropathy and appears to be related to daily, but not cumulative, doses.
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PMID:Clinical pharmacokinetics of stavudine. 934 3

The nucleoside drug lamivudine (3TC) triggers the selection of resistant forms of the human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT) with a substitution of amino acid 184Met. The 3TC-resistant RT enzymes 184Val and 184Ile exhibit a processivity defect in in vitro assays that correlates with reduced replication of the corresponding virus variants in primary cells. However, no replication defect is apparent for these two mutants in the transformed T-cell line SupT1. One obvious difference between the two cell types is the intracellular deoxynucleoside triphosphate (dNTP) level. Primary cells have a much smaller dNTP pool, and this cellular condition may emphasize the processivity defect of the codon 184 RT variants. Alternatively, cell-specific cofactors that influence the process of reverse transcription may exist. Such accessory factors may be packaged into the virion to exert an effect on the RT enzyme. To discriminate between these possibilities we performed additional assays with the wild-type and mutant RT enzymes. The RT proteins were either isolated from virions produced by primary and transformed cell types or expressed as recombinant protein. We also performed infection assays with cells treated with a drug that reduces the intracellular dNTP pool. Furthermore, reverse transcription was studied within virus particles in the endogenous assay, which allows for the manipulation of the dNTP level. The combined results indicate that the enzymatic defect of the 3TC-resistant HIV-1 variants is stressed at low dNTP concentrations.
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PMID:Limiting deoxynucleoside triphosphate concentrations emphasize the processivity defect of lamivudine-resistant variants of human immunodeficiency virus type 1 reverse transcriptase. 937 54

The template for synthesis of hepadnaviral RNAs is a covalently closed circular (ccc) DNA located in the nucleus of the infected hepatocyte. Hepatocytes are normally long-lived and nondividing, and antiviral therapies in chronically infected individuals face the problem of eliminating not only the replicative forms of viral DNA found in the cytoplasm but also the cccDNA from the nucleus. Because cccDNA does not replicate semiconservatively, it is not an obvious target for antiviral therapy. However, elimination of cccDNA might be facilitated if its half-life were short in comparison to the generation time of hepatocytes and if new cccDNA formation were effectively blocked. We have therefore measured cccDNA levels in woodchuck hepatocyte cultures following in vitro infection with woodchuck hepatitis virus and treatment with inhibitors of viral DNA synthesis. The viral reverse transcriptase inhibitors lamivudine (3TC) [(-)-beta-L-2',3'-dideoxy-3'-thiacytidine), FTC (5-fluoro-2',3'-dideoxy-3'-thiacytidine) and ddC (2',3'-dideoxycytidine) were added to the cultures beginning at 4 days postinfection. Treatment for up to 36 days with 3TC reduced the amount of cccDNA in the cultures not more than twofold compared to that of an untreated control. Treatment with ddC for 36 days and with FTC for 12 days resulted in effects similar to that of treatment with 3TC. Moreover, the declines in cccDNA appeared to reflect the loss of hepatocytes from the cultures rather than of cccDNA from hepatocytes. These results emphasize the important role of the longevity of the infected hepatocytes in the persistence of an infection.
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PMID:Lack of effect of antiviral therapy in nondividing hepatocyte cultures on the closed circular DNA of woodchuck hepatitis virus. 937 99

We compared the development of resistance toward BI-RG-587 (nevirapine) and alpha-APA R89439 (loviride) starting from the wild-type HIV-1 strain IIIB and the 3TC-resistant HIV-1 strain containing the M184V mutation. The reverse transcriptase of the M184V mutant has been reported to have a higher fidelity. Our experiments showed that there was no significant delay in virus breakthrough of the M184V mutant as compared with the wild-type virus. We therefore conclude that the reported higher fidelity of the M184V mutant does not lead to a delay in the development of resistance to the nonnucleoside reverse transcriptase inhibitors nevirapine and loviride.
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PMID:Lamivudine resistance of HIV type 1 does not delay development of resistance to nonnucleoside HIV type 1-specific reverse transcriptase inhibitors as compared with wild-type HIV type 1. 949 15


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