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)

Genomic rearrangements in the 5' part of the human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT) have been involved in multidrug resistance to nucleoside RT inhibitors (NRTI). We carried out a retrospective, multicenter study to investigate the prevalence, variability, and phenotypic consequences of such rearrangements. Data concerning the HIV-1 RT genotype and the biological and clinical characteristics of NRTI-treated patients were collected from 10 virology laboratories. Sensitivities of the different HIV-1 variants to RT inhibitors were analyzed in a single-cycle recombinant virus assay. Fifty-two of 2,152 (2.4%) RT sequences had a rearrangement in the 5' part of the RT, with an extensive molecular variation. The number of codons inserted between positions 68 and 69 ranged from 1 (3 samples) or 2 (41 samples) to 5 and 11 in one case each. In four cases, codon 67 was deleted. High levels of phenotypic resistance to zidovudine (AZT), lamivudine (3TC), stavudine (d4T), abacavir (ABC), and didanosine (ddI) were found in 95, 92, 72, 62, and 15% of the 40 samples analyzed, respectively. Resistance to AZT, d4T, and ABC could be found in the absence of the T215Y/F mutations. Resistance to 3TC could develop in the absence of specific mutations. Low-level resistance to ddI was noticed in 40% of the patients. The deletions of codon 67 seemed to have little effect on NRTI sensitivity. Most of the rearrangements were shown to contribute to cross-resistance to NRTI. The results regarding susceptibility to ddI raise the question of the interpretation of the phenotypic data concerning this drug.
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PMID:Genotypic and phenotypic resistance patterns of human immunodeficiency virus type 1 variants with insertions or deletions in the reverse transcriptase (RT): multicenter study of patients treated with RT inhibitors. 1135 34

When human immunodeficiency virus type 1 (HIV-1) is selected for resistance to 3TC, the methionine normally present at position 184 is replaced by valine or isoleucine. Position 184 is the X of the conserved YXDD motif; positions 185 and 186 form part of the triad of aspartic acids at the polymerase active site. Structural and biochemical analysis of 3TC-resistant HIV-1 reverse transcriptase (RT) led to a model in which a beta-branched amino acid at position 184 would act as a steric gate. Normal deoxynucleoside triphosphates (dNTPs) could still be incorporated; the oxathiolane ring of 3TCTP would clash with the beta branch of the amino acid at position 184. This model can also explain 3TC resistance in feline immunodeficiency virus and human hepatitis B virus. However, it has been reported (14) that murine leukemia viruses (MLVs) with valine (the amino acid present in the wild type), isoleucine, alanine, serine, or methionine at the X position of the YXDD motif are all resistant to 3TC. We prepared purified wild-type MLV RT and mutant MLV RTs with methionine, isoleucine, and alanine at the X position. The behavior of these RTs was compared to those of wild-type HIV-1 RT and of HIV-1 RT with alanine at the X position. If alanine is present at the X position, both MLV RT and HIV-1 RT are relatively resistant to 3TCTP in vitro. However, the mutant enzymes were impaired relative to their wild-type counterparts; there appears to be steric hindrance for both 3TCTP and normal dNTPs.
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PMID:YADD mutants of human immunodeficiency virus type 1 and Moloney murine leukemia virus reverse transcriptase are resistant to lamivudine triphosphate (3TCTP) in vitro. 1141 98

The chemotherapy of virus infections has definitely come of age. There are now 15 antiviral agents that have been formally licensed for the treatment of human immunodeficiency virus infections (zidovudine, didanosine, zalcitabine, stavudine, lamivudine, abacavir, nevirapine, delavirdine, efavirenz, saquinavir, ritonavir, indinavir, nelfinavir, amprenavir, lopinavir) and several others, such as tenofovir disoproxil, emtricitabine, capravirine, emivirine, T-20 (pentafuside) and AMD3100 (bicyclam) are under clinical development. Lamivudine has been approved, and several other compounds (such as adefovir dipivoxil, emtricitabine and entecavir) are under clinical development, for the treatment of hepatitis B virus infections. Among the anti-herpesvirus agents, aciclovir, valaciclovir, penciclovir, famciclovir, idoxuridine, trifluridine and brivudin are used in the treatment of herpes simplex virus and varicella-zoster virus infections, and ganciclovir, foscarnet, cidofovir, fomivirsen and maribavir (the latter in the developmental stage) are used in the treatment of cytomegalovirus infections. Following amantadine and rimantadine, the neuraminidase inhibitors, zanamivir and oseltamivir, have now become available for the therapy and prophylaxis of influenza virus infections, and so is ribavirin for the treatment of respiratory syncytial virus infections and the combination of ribavirin with interferon-alpha for the treatment of hepatitis C virus infections.
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PMID:Antiviral drugs: current state of the art. 1141 55

Human foamy virus (HFV), a retrovirus of simian origin which occasionally infects humans, is the basis of retroviral vectors in development for gene therapy. Clinical considerations of how to treat patients developing an uncontrolled infection by either HFV or HFV-based vectors need to be raised. We determined the susceptibility of the HFV to dideoxynucleosides and found that only zidovudine was equally efficient against the replication of human immunodeficiency virus type 1 (HIV-1) and HFV. By contrast, zalcitabine (ddC), lamivudine (3TC), stavudine (d4T), and didanosine (ddI) were 3-, 3-, 30-, and 46-fold less efficient against HFV than against HIV-1, respectively. Some amino acid residues known to be involved in HIV-1 resistance to ddC, 3TC, d4T, and ddI were found at homologous positions of HFV reverse transcriptase (RT). These critical amino acids are located at the same positions in the three-dimensional structure of HIV-1 and HFV RT, suggesting that both enzymes share common patterns of inhibition.
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PMID:Efficacy of dideoxynucleosides against human foamy virus and relationship to its reverse transcriptase amino acid sequence and structure. 1143 99

This report updates and consolidates all previous U.S. Public Health Service recommendations for the management of health-care personnel (HCP) who have occupational exposure to blood and other body fluids that might contain hepatitis B virus (HBV), hepatitis C virus (HCV), or human immunodeficiency virus (HIV). Recommendations for HBV postexposure management include initiation of the hepatitis B vaccine series to any susceptible, unvaccinated person who sustains an occupational blood or body fluid exposure. Postexposure prophylaxis (PEP) with hepatitis B immune globulin (HBIG) and/or hepatitis B vaccine series should be considered for occupational exposures after evaluation of the hepatitis B surface antigen status of the source and the vaccination and vaccine-response status of the exposed person. Guidance is provided to clinicians and exposed HCP for selecting the appropriate HBV PEP. Immune globulin and antiviral agents (e.g., interferon with or without ribavirin) are not recommended for PEP of hepatitis C. For HCV postexposure management, the HCV status of the source and the exposed person should be determined, and for HCP exposed to an HCV positive source, follow-up HCV testing should be performed to determine if infection develops. Recommendations for HIV PEP include a basic 4-week regimen of two drugs (zidovudine [ZDV] and lamivudine [3TC]; 3TC and stavudine [d4T]; or didanosine [ddI] and d4T) for most HIV exposures and an expanded regimen that includes the addition of a third drug for HIV exposures that pose an increased risk for transmission. When the source person's virus is known or suspected to be resistant to one or more of the drugs considered for the PEP regimen, the selection of drugs to which the source person's virus is unlikely to be resistant is recommended. In addition, this report outlines several special circumstances (e.g., delayed exposure report, unknown source person, pregnancy in the exposed person, resistance of the source virus to antiretroviral agents, or toxicity of the PEP regimen) when consultation with local experts and/or the National Clinicians' Post-Exposure Prophylaxis Hotline ([PEPline] 1-888-448-4911) is advised. Occupational exposures should be considered urgent medical concerns to ensure timely postexposure management and administration of HBIG, hepatitis B vaccine, and/or HIV PEP.
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PMID:Updated U.S. Public Health Service Guidelines for the Management of Occupational Exposures to HBV, HCV, and HIV and Recommendations for Postexposure Prophylaxis. 1144 29

Nucleoside reverse-transcriptase (RT) inhibitors (NRTIs), including lamivudine (3TC) and zidovudine (Zdv), are being evaluated for the treatment of human T cell lymphotropic virus type 1 (HTLV-1)-associated disease. However, information on the susceptibility of HTLV-1 to these drugs is limited. The activity of 5 NRTIs on HTLV-1 RT was evaluated. IC(50) values for Zdv, zalcitabine (ddC), didanosine (ddI), 3TC, and stavudine (d4T) were determined, using an enzymatic assay, for 5 HTLV-1 isolates and for reference wild-type and NRTI-resistant human immunodeficiency virus type 1 (HIV-1). Both HTLV-1 and wild-type HIV-1 were equally susceptible to Zdv, ddC, ddI, and d4T. In contrast, high-level resistance to 3TC was found in all HTLV-1 isolates. The findings support the clinical use of Zdv, ddC, ddI, and d4T but not of 3TC for the antiretroviral treatment of HTLV-1-associated disease.
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PMID:Susceptibility of human T cell leukemia virus type 1 to reverse-transcriptase inhibitors: evidence for resistance to lamivudine. 1147 Nov 10

Retroviruses may cause diseases in their vertebrate hosts. They are distinguished by their common means of replication involving reverse transcription, a process inhibited by nucleoside reverse transcriptase inhibitors (NRTIs) and other compounds used in antiretroviral chemotherapy. Previous work on NRTIs has been limited to their effect on human immunodeficiency virus (HIV) (for review see Ho & Hitchcock, 1989; Weller, 1999) and little information exists regarding the efficacy and therapeutic potential of these drugs against other retroviruses. We have tested all six NRTIs licensed for HIV treatment [didanosine (ddI), zalcitabine (ddC), lamivudine (3TC), stavudine (d4T), zidovudine (AZT) and abacavir (ABC)] against seven retroviruses representative of the traditional subfamilies: Spumavirinae, Lentivirinae and the Oncovirinae. As expected, each drug showed a range of activities against the panel of retroviruses, some drugs inhibiting other viruses at concentrations well below those required for HIV. Overall, AZT was the most active inhibitor (IC50 range, 0.032-1.0 microM), being most active against the Spuma (foamy) viruses. Abacavir was inhibitory for HIV-1, MN strain (HIV-1 MN), amphotrophic murine leukemia virus (MLV-A) and simian foamy virus type 6 (SFV-6). The least effective inhibitor, 3TC (IC50 range, 0.32->100 microM), was most potent against simian retrovirus types 1 and 2 (SRV-1, SRV-2) and HIV-1, but did not inhibit foamy viruses and MLV-A. Additionally, there were differences in the concentration of drug required to inhibit closely related viruses. Taken together, these data suggest that NRTIs have a wide spectrum of antiretroviral activity and the activity of compounds, even against closely related retroviruses, cannot be predicted.
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PMID:Differential susceptibility of retroviruses to nucleoside analogues. 1152 46

A method employing capillary electrophoresis (CE) with tandem mass spectrometry (MS) has been developed for the simultaneous determination, on one hand, of zidovudine (AZT) with stavudine (d4T), and on the other hand, of lamivudine (3TC) with a didanosine metabolite (ddA), four potent human immunodeficiency virus reverse transcriptase (RT-HIV) inhibitors. The influence of several parameters (pH and ionic strength of volatile formic acid-ammonia buffer) as well as the influence of magnesium cation upon electroosmotic flow, electrophoretic mobility and peak efficiency has been studied. The limit of detection (LOD) by this method is 2.5 ppb for AZT and 20 ppb for d4T, 2 ppb for ddA and 5 ppb for 3TC, respectively. This paper illustrates the current importance in CE-ESI/MS/MS technique as a complementary or substituted method to measure levels (at ng/mL) of anti-HIV drugs alone or in combination.
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PMID:Analysis of anti-HIV nucleoside inhibitors by capillary electrophoresis-electrospray ionization mass spectrometry. 1156 50

In view of close similarities at the molecular and clinical levels, feline immunodeficiency virus (FIV) infection of the domestic cat is subject of increasing attention as an animal model for human immunodeficiency virus (HIV) infection. A range of reverse transcriptase inhibitors effective against HIV are also active against FIV, allowing successful use of the cat model to investigate drug interactions and resistance development. Nevertheless, while combined nucleoside analog and protease inhibitor usage has proven remarkably effective in treating HIV infection, combination antiretroviral therapy of FIV infection has been hampered by lack of protease inhibitors specific for FIV. In an attempt to circumvent this problem, we have examined the feasibility of applying in the FIV system combination protocols lacking a protease inhibitor. We now report that, as observed during HIV infection, the nucleoside analog abacavir (ABC or 1592U89) is able to effectively block in vitro FIV-replication. Furthermore, we demonstrate that combined usage of ABC with the nucleoside analogs zidovudine (ZDV or AZT) and lamivudine (3TC) also blocks in vitro FIV replication in a synergistic manner. However, in contrast to its effect on HIV replication, the ribonucleotide reductase inhibitor hydroxyurea (HU) is unable to effectively control in vitro FIV replication.
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PMID:Combined effect of zidovudine (ZDV), lamivudine (3TC) and abacavir (ABC) antiretroviral therapy in suppressing in vitro FIV replication. 1168 14

Individuals coinfected with human immunodeficiency virus 1 (HIV-1) and hepatitis B virus (HBV) often receive treatment with an antiretroviral regimen including lamivudine. Lamivudine monotherapy for HBV may lead to drug-resistant mutations in a significant number of patients. The virological and biochemical responses of 8 patients coinfected with HBV/HIV-1 treated with both lamivudine and famciclovir were studied. Patients exhibiting HBV viral rebound at 1 year were analyzed for the emergence of HBV polymerase mutations. Only 1 patient had no prior exposure to lamivudine. Addition of famciclovir to the treatment regimen resulted in a median fall in HBV DNA level of 0.33 log(10) at 3 months and an overall rise in HBV DNA level of 3 log(10) at 12 months. The only patient in whom durable viral suppression and HBV e antigen seroconversion were noted began receiving lamivudine and famciclovir simultaneously. HBV polymerase gene sequencing identified resistance-associated mutations in 6 of 7 patients with viral rebound. Sequential nucleoside analogue therapy is unlikely to be successful in achieving long-term suppression of HBV replication, and combination therapy should be considered at treatment initiation.
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PMID:Failure of combination therapy with lamivudine and famciclovir following lamivudine monotherapy for hepatitis B virus infection in patients coinfected with human immunodeficiency virus-1. 1169 87


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