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: UMLS:C0021051 (immunodeficiency)
71,517 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The genetic resistance to nucleoside inhibitors of the reverse transcriptase (RT) of human immunodeficiency virus I (HIV-1) isolates in the Czech Republic was examined by a line probe assay (LiPA) and nucleotide sequencing. The results of LiPA analysis of 294 blood specimens obtained from 156 patients revealed a high incidence of mutations in the RT gene related to resistance to various drugs (67.3%) in various combinations. Mutations in RT gene (M41L, K70R and T215Y/F) conferring the resistance to zidovudine (ZDV) were most frequent (62.6%), that (M184V) responsible for the resistance to lamivudine (3TC) was less frequent (33.7%), while those linked to the resistance to dideoxyinosine (ddl) and dideoxyinosine together with dideoxycytidine (ddl/ddC) were rather rare (6.5% and 5.1%, respectively). LiPA gave a high rate of uninterpretable results due to codon hybridization failure, especially in HIV-1 isolates of non-B subtype. Thirty-two specimens were analyzed also by direct sequencing of a part of RT gene. The results obtained by LiPA and the sequencing were highly concordant for codons successfully analyzed by both methods, but the sequencing provided information also about the codons that could not be analyzed by LiPA. A high prevalence of resistant strains in the Czech Republic and their heterogeneity justifies a regular HIV-1 resistance testing. LiPA turned out as a fast, powerful and most reliable tool for such a purpose. However, due to an increasing diversity of HIV-1 strains circulating in the Czech Republic, LiPA cannot replace the nucleotide sequence analysis.
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PMID:Human immunodeficiency virus 1 strains resistant to nucleoside inhibitors of reverse transcriptase in isolates from the Czech Republic as monitored by line probe assay and nucleotide sequencing. 1208 26

Virtually all the compounds that are currently used, or are subject of advanced clinical trials, for the treatment of human immunodeficiency virus (HIV) infections, belong to one of the following classes: (i) nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs): i.e. zidovudine (AZT), didanosine (ddI), zalcitabine (ddC), stavudine (d4T), lamivudine (3TC), abacavir (ABC), emtricitabine [(-)FTC], tenofovir disoproxil fumarate; (ii) non-nucleoside reverse transcriptase inhibitors (NNRTIs): i.e. nevirapine, delavirdine, efavirenz, emivirine; and (iii) protease inhibitors (PIs): i.e. saquinavir, ritonavir, indinavir, nelfinavir, amprenavir and lopinavir. In addition to the reverse transcriptase (RT) and protease reaction, various other events in the HIV replicative cycle can be considered as potential targets for chemotherapeutic intervention: (i) viral adsorption, through binding to the viral envelope glycoprotein gp120 (polysulfates, polysulfonates, polycarboxylates, polyoxometalates, polynucleotides, and negatively charged albumins); (ii) viral entry, through blockade of the viral coreceptors CXCR4 [bicyclam (AMD3100) derivatives] and CCR5 (TAK-779 derivatives); (iii) virus-cell fusion, through binding to the viral envelope glycoprotein gp41 (T-20, T-1249); (iv) viral assembly and disassembly, through NCp7 zinc finger-targeted agents [2,2'-dithiobisbenzamides (DIBAs), azadicarbonamide (ADA)]; (v) proviral DNA integration, through integrase inhibitors such as 4-aryl-2,4-dioxobutanoic acid derivatives; (vi) viral mRNA transcription, through inhibitors of the transcription (transactivation) process (flavopiridol, fluoroquinolones). Also, various new NRTIs, NNRTIs and PIs have been developed that possess, respectively: (i) improved metabolic characteristics (i.e. phosphoramidate and cyclosaligenyl pronucleotides by-passing the first phosphorylation step of the NRTIs), (ii) increased activity ["second" or "third" generation NNRTIs (i.e. TMC-125, DPC-083)] against those HIV strains that are resistant to the "first" generation NNRTIs, or (iii) as in the case of PIs, a different, nonpeptidic scaffold [i.e. cyclic urea (mozenavir), 4-hydroxy-2-pyrone (tipranavir)]. Nonpeptidic PIs may be expected to inhibit HIV mutant strains that have become resistant to peptidomimetic PIs. Given the multitude of molecular targets with which anti-HIV agents can interact, one should be cautious in extrapolating the mode of action of these agents from cell-free enzymatic assays to intact cells. Two examples in point are L-chicoric acid and the nonapeptoid CGP64222, which were initially described as an integrase inhibitor or Tat antagonist, respectively, but later shown to primarily act as virus adsorption/entry inhibitors, the latter through blockade of CXCR4.
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PMID:New developments in anti-HIV chemotherapy. 1208 68

Among the acquired immunodeficiency syndrome (AIDS) drugs approved by the FDA for clinical use, two are modified cytosine analogs, Zalcitabine (ddC) and Lamivudine [(-)3TC]. (-)3TC is the only analog containing an unnatural L (-) nucleoside configuration. Similar to other dideoxy nucleosides, these analogs are metabolically activated to the triphosphate that is incorporated into DNA by human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT) resulting in DNA chain termination and ultimately cessation of viral replication. The natural D (+) 3TC isomer also acts in a similar manner to inhibit HIV-1 RT. In cell culture, (-)3TC is less toxic than its D (+) isomer, (+)3TC, containing the natural nucleoside configuration, and both are considerably less toxic than 2',3'-dideoxycytidine (ddC). The mechanistic basis for the stereochemical selectivity and differential toxicity of the isomeric 2',3'-dideoxy-3'-thiacytidine (3TC) and ddC compounds is not completely understood although a number of factors may clearly come into play. We have previously investigated the mechanistic basis for the differential stereoselective inhibition and toxicity of these three cytosine analogs by comparing the effects of 2',3'-deoxycytidine-5'-triphosphate (ddCTP), beta-D-(+)-2'3'-dideoxy-3'-thiacytidine-5'-triphosphate [(+)3TC-TP] and beta-L-(-)-2'3'-dideoxy-3'-thiacytidine-5'-triphosphate [(-)3TC-TP] on the HIV-1 RT as well as a recombinant form of the human mitochondrial DNA polymerase gamma (Pol gamma), the holoenzyme polymerase responsible for mitochondrial DNA replication. In this review, we discuss studies which may provide insight into the molecular mechanism for the stereochemical selectivity and differential toxicity.
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PMID:Perspectives on the molecular mechanism of inhibition and toxicity of nucleoside analogs that target HIV-1 reverse transcriptase. 1208 71

This retrospective cohort study investigated whether particular antiretroviral agents are associated with a higher risk for developing grade 4 liver enzyme elevations (LEEs) in patients with human immunodeficiency virus (HIV) type 1 infection who are starting to receive highly active antiretroviral therapy (HAART). Grade 4 LEE was defined as aminotransferase levels >10 times the upper limit of normal and >200 U above baseline levels. A multivariate Cox model was used to identify risk factors. The incidence of LEE was 6.3%. No patients died of LEE consequences. Risk factors were higher baseline alanine aminotransferase levels, chronic hepatitis B or C virus infection, antiretroviral therapy-naive patients undergoing their first HAART regimen, recent start of a regimen of nevirapine or high-dose ritonavir, and female sex. In hepatitis B virus (HBV)-coinfected patients, discontinuing lamivudine (3TC) use was a risk factor. In 97% of cases, >or=1 risk factor was present. In HBV-coinfected patients using 3TC, continued use of 3TC should be considered, even if 3TC-resistant HIV strains develop.
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PMID:Incidence of and risk factors for severe hepatotoxicity associated with antiretroviral combination therapy. 1208 58

The AIDS Clinical Trials Group Study 850 (ACTG 850) evaluated the penetration of zidovudine (ZDV), lamivudine (3TC), and amprenavir (APV), given alone and in combination with the 2 nucleoside analogues, into the male genital tract, because these factors may affect human immunodeficiency virus (HIV) type 1 suppression and transmission. Nineteen men receiving APV monotherapy and 12 men receiving triple therapy donated blood plasma (BP) and seminal plasma (SP) during therapy. Paired SP and BP were used to calculate compartmental concentration ratios. APV SP concentrations were consistently lower than BP concentrations, ZDV SP concentrations approximated BP concentrations early but became greater later in the dosing interval, and 3TC SP concentrations were substantially greater than BP concentrations throughout. Observed SP concentrations plotted with population BP concentration-time curves confirmed these findings, suggesting that passive diffusion (APV), slowed elimination (ZDV), and either active accumulation and/or inhibition of elimination (3TC) are responsible for SP concentrations of these agents. The antiretroviral effect of APV monotherapy was related to APV concentrations.
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PMID:The pharmacokinetics of amprenavir, zidovudine, and lamivudine in the genital tracts of men infected with human immunodeficiency virus type 1 (AIDS clinical trials group study 850). 1213 55

Although anti-human immunodeficiency virus type 1 (HIV-1) therapy has prolonged the lives of patients, drug resistance is a significant problem. Of particular concern are mutations that cause cross-resistance to a particular class of drugs. Among the mutations that cause resistance to several nucleoside analogs are the insertion of amino acids in the fingers subdomain of HIV-1 reverse transcriptase (RT) at positions 69 and 70. These insertions are usually associated with changes in the flanking amino acids and with a change to F or Y at position 215. We have proposed that the T215F/Y mutation makes the binding of ATP to HIV-1 RT more effective, which increases the excision of 3-azido-3'-deoxythymidine-5'-monophosphate (AZTMP) in vitro and increases zidovudine (AZT) resistance in vivo. Although the mechanism of AZT resistance involves enhanced excision, resistance to 3TC involves a block to incorporation of the analog. We measured the effects of fingers insertion mutations on the misincorporation and excision of several nucleoside analogs. RT variants with the amino acid insertions in the fingers and T215Y have a decreased level of misincorporation of ddATP and 3TCTP. These mutants also have the ability to excise AZTMP by ATP-dependent pyrophosphorylysis. However, unlike the classic AZT resistance mutations (M41L/D67N/K70R/T215Y or F/K219E or Q), the combination of the amino acid insertions in the fingers and the T215Y mutation allows efficient excision of ddTMP and d4TMP, even when relatively high levels of deoxynucleoside triphosphates are present in the reaction. Although the dideoxynucleoside analogs of other nucleosides were excised more slowly than AZTMP, ddTMP, and d4TMP, the mutants with the fingers insertion and T215Y excised all of the nucleoside analogs that were tested more efficiently than wild-type RT or a mutant RT carrying the classical AZT resistance mutations. In the ternary complex (RT/template-primer/dNTP), the presence of the bound dNTP prevents the end of the primer from gaining access to the nucleotide binding site (N site) where excision occurs. Gel shift analysis showed that the amino acid insertions in the fingers destabilized the ternary complex compared to wild-type HIV-1 RT. If the ternary complex is unstable, the end of the primer can gain access to the N site and excision can occur. This could explain the enhanced excision of the nucleoside analogs.
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PMID:Nucleoside analog resistance caused by insertions in the fingers of human immunodeficiency virus type 1 reverse transcriptase involves ATP-mediated excision. 1218 98

Mother-to-child transmission of the human immunodeficiency virus is substantially reduced by prenatal and postnatal treatment with anti-retroviral nucleoside analogues; however, the long-term consequences of these drug interventions are not known. The nucleoside analogue zidovudine (3'-azido-2',3'-dideoxythymidine; AZT) is carcinogenic in mice when administered transplacentally or neonatally, and this may be due to a genotoxic mechanism. Since single-drug treatment with AZT is being superseded by multidrug combinations, we have investigated the induction of mutations and micronuclei in mice treated neonatally with AZT, lamivudine (3'-thia-2',3'-dideoxycytidine; 3TC), or a combination of the two drugs. B6C3F(1)/Tk+/- mice were treated daily from days 1-8 of age with 200 mg AZT/kg/day, 200 mg 3TC/kg/day, or a mixture of 200 mg AZT + 200 mg 3TC/kg/day (AZT/3TC). One and 2 days after the last dose, bone marrow was collected to assess the induction of micronuclei in polychromatic erythrocytes; 3 weeks following treatment, the induction of mutants was determined in the hypoxanthine-guanine phosphoribosyltransferase (Hprt) and thymidine kinase (Tk) genes of spleen lymphocytes. AZT and AZT/3TC, but not 3TC, caused a significant increase in micronuclei, with the response being greatest one day after the last dose. None of the drugs induced mutations in the Hprt gene, while AZT and AZT/3TC, but not 3TC, caused a significant increase in the Tk mutant frequency. The increase in Tk mutants by AZT and AZT/3TC was associated with loss of the wild-type (Tk+) allele (loss of heterozygosity). These data suggest that AZT, but not 3TC, is genotoxic in neonatal mice, and that 3TC does not alter significantly the responses observed with AZT alone.
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PMID:Frequency of Tk and Hprt lymphocyte mutants and bone marrow micronuclei in B6C3F(1)/Tk+/- mice treated neonatally with zidovudine and lamivudine. 1218 83

We compared use of a 3-class regimen (nevirapine [Nvp], stavudine [d4T], and indinavir [Idv; 1000 mg 3 times daily]) with use of a 2-class regimen (lamivudine [3TC], d4T, and Idv [800 mg 3 times daily]) for 145 patients infected with human immunodeficiency virus type 1 (HIV-1). At week 72, the plasma HIV-1 RNA level was undetectable in 52% of Nvp recipients versus 79% of 3TC recipients (P<.001). Idv trough levels were 81 ng/mL in the Nvp group and 99 ng/mL in the 3TC group (P=.012). In the Nvp group, 42.5% of patients discontinued the study regimen; in the 3TC group, 22.5% of patients discontinued therapy (P=.013). The rate of resistance to nonnucleoside analogue reverse-transcriptase inhibitors among patients in the Nvp group with virological failure was not different from the rate of resistance to 3TC among patients in the 3TC group with virological failure. These results do not support the use of a 3-class regimen that includes Nvp for patients with no or limited exposure to nucleoside analogues.
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PMID:Nevirapine or lamivudine plus stavudine and indinavir: examples of 2-class versus 3-class regimens for the treatment of human immunodeficiency virus type 1. 1238 44

A significant proportion of human immunodeficiency virus (HIV) infected patients are coinfected with hepatitis B virus (HBV). Currently available treatments for chronic hepatitis B (interferon [IFN]-alpha and lamivudine [3TC]) have limited long-term utility because of side effects or of the development of resistance. Tenofovir disoproxil fumarate (TDF) is a nucleotide analog with excellent activity in vitro against HBV, which is also active against 3TC-resistant HBV variants. In this 24-week pilot study, the anti-HBV activity of TDF was prospectively evaluated in a cohort of 6 HIV coinfected subjects for whom 3TC and IFN therapy had previously failed. At baseline, all patients were taking 3TC or FTC and were hepatitis B surface antigen and hepatitis B e antigen positive; 4 had cirrhosis. Baseline HBV load was 7.95 log(10) copies/mL. By weeks 12 and 24, HBV load had decreased by 3.1 log(10) copies/mL and 4.3 log(10) copies/mL, respectively. There was a transient increase of transaminases after the initiation of treatment. No patient developed HBe antibodies. TDF is a very promising drug for the treatment of chronic hepatitis B in HIV-infected individuals.
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PMID:Tenofovir disoproxil fumarate therapy for chronic hepatitis B in human immunodeficiency virus/hepatitis B virus-coinfected individuals for whom interferon-alpha and lamivudine therapy have failed. 1244 73

The methionine-to-valine mutation in codon 184 (M184V) in reverse transcriptase (RT) of human immunodeficiency virus type 1 (HIV-1) or simian immunodeficiency virus (SIV) confers resistance to (-)-2'-deoxy-3'-thiacytidine (3TC; lamivudine) and increased sensitivity to 9-[2-(phosphonomethoxy)propyl]adenine (PMPA; tenofovir). We have used the SIV model to evaluate the effect of the M184V mutation on the emergence of resistance to the combination of 3TC plus PMPA. A site-directed mutant of SIVmac239 containing M184V (SIVmac239-184V) was used to select for resistance to both 3TC and PMPA by serial passage in the presence of increasing concentrations of both drugs. Under these selection conditions, the M184V mutation reverted in the majority of the selections. Variants resistant to both drugs were found to have the lysine-to-arginine mutation at codon 65 (K65R), which has previously been associated with resistance to PMPA in both SIV and HIV. Similarly, in rhesus macaques infected with SIVmac239-184V for 46 weeks and treated daily with (-)-2'-deoxy-5-fluoro-3'-thiacytidine [(-)-FTC], there was no reversion of M184V, but this mutation reverted to 184 M in all three animals within 24 weeks of treatment with (-)-FTC and PMPA. Although the addition of PMPA to the (-)-FTC therapy induced a decrease in virus loads in plasma, these loads eventually returned to pre-PMPA levels in each case. All animals receiving this combination developed the K65R mutation. These results demonstrate that the combination of PMPA with 3TC or (-)-FTC selects for the K65R mutation and against the M184V mutation in SIV RT.
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PMID:Reversion of the M184V mutation in simian immunodeficiency virus reverse transcriptase is selected by tenofovir, even in the presence of lamivudine. 1250 28


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