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)

Six cases of post-operative erythroderma after open heart surgery are described. About 10 days after seemingly uneventful recovery, all patients developed fever, erythroderma, liver enzyme elevation, pancytopenia, and an aplastic bone marrow. Their condition rapidly deteriorated, and they died within 20 days of the onset of symptoms. Skin biopsy specimens from two patients showed mild leukocytic infiltration in the epidermal basal layer and upper dermis. Immunostaining by the ABC method showed that most of these infiltrating cells were suppressor/cytotoxic T cells. HLA study of peripheral lymphocytes from two patients and their families revealed that the patients' HLA phenotypes were incompatible from their children's HLA findings. Y chromatin was present in the lymphocytes of the skin biopsy specimen of a female patient. Based on the clinical picture, skin biopsy, HLA study, and Y chromatin study, the authors strongly suspect post-transfusion GVHD as the etiology of postoperative erythroderma, although these patients lacked any known immunodeficiency.
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PMID:Post-transfusion graft-versus-host disease following open heart surgery. Report of six cases. 252 50

Resistance to antifungal drugs, specifically azoles such as fluconazole, in the opportunistic yeast Candida albicans has become an increasing problem in human immunodeficiency virus (HIV)-infected individuals. The molecular mechanisms responsible for this resistance have only recently become apparent and can include alterations in the target enzyme of the azole drugs (lanosterol 14alpha demethylase [14DM]), or in various efflux pumps from both the ABC transporter and major facilitator gene families. To determine which of these possible mechanisms was associated with the development of drug resistance in a particular case, mRNA levels have been studied in a series of 17 clinical isolates taken from a single HIV-infected patient over 2 years, during which time the levels of fluconazole resistance of the strain increased over 200-fold. Using Northern blot analysis of steady-state levels of total RNA from these isolates, we observed increased mRNA levels of ERG16 (the 14DM-encoding gene), CDR1 (an ABC transporter), and MDR1 (a major facilitator) in this series. The timing of the increase in mRNA levels of each of these genes correlated with increases in fluconazole resistance of the isolates. Increased mRNA levels were not observed for three other ABC transporters, two other genes in the ergosterol biosynthetic pathway, or the NADPH-cytochrome P-450 oxidoreductase gene that transfers electrons from NADPH to 14DM. Increases in mRNA levels of ERG16 and CDR1 correlated with increased cross-resistance to ketoconazole and itraconazole but not to amphotericin B. A compilation of the genetic alterations identified in this series suggests that resistance develops gradually and is the sum of several different changes, all of which contribute to the final resistant phenotype.
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PMID:Increased mRNA levels of ERG16, CDR, and MDR1 correlate with increases in azole resistance in Candida albicans isolates from a patient infected with human immunodeficiency virus. 921 Jun 70

Sequential Candida glabrata isolates were obtained from the mouth of a patient infected with human immunodeficiency virus type 1 who was receiving high doses of fluconazole for oropharyngeal thrush. Fluconazole-susceptible colonies were replaced by resistant colonies that exhibited both increased fluconazole efflux and increased transcripts of a gene which codes for a protein with 72.5% identity to Pdr5p, an ABC multidrug transporter in Saccharomyces cerevisiae. The deduced protein had a molecular mass of 175 kDa and was composed of two homologous halves, each with six putative transmembrane domains and highly conserved sequences of ATP-binding domains. When the earliest and most azole-susceptible isolate of C. glabrata from this patient was exposed to fluconazole, increased transcripts of the PDR5 homolog appeared, linking azole exposure to regulation of this gene.
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PMID:Fluconazole resistance associated with drug efflux and increased transcription of a drug transporter gene, PDH1, in Candida glabrata. 966 Oct 6

Increased activation of CD8+ T cells, particularly increased expression of CD38 antigen, has been shown to strongly correlate with progression of human immunodeficiency virus-positive (HIV+) individuals to acquired immunodeficiency syndrome (AIDS) and death. As part of a study evaluating responses to a recombinant gp160 vaccine, we have used quantitative three-color flow cytometry (QFCM) to further investigate the relationships among several measures of lymphocyte activation/immunological status. Parameters evaluated included 1) absolute circulating counts for the major lymphocyte phenotypes (T, B, NK) and selected activated/regulatory subsets believed to have clinical value in the monitoring of patients with HIV infection; 2) level of CD38 expression (antibody-binding capacity [ABC]) on the lymphocyte subsets defined by CD8, CD38, and HLA-DR; and 3) serum levels of soluble CD8. CD8+DR+CD38+ counts were found to be markedly increased (approximately 10-fold) in HIV+ individuals, whereas CD4+CD45RA+ counts were markedly decreased (approximately 5-fold). We confirmed previous reports that CD38 expression on CD8 T cells (here reported as CD38 ABC) are increased in asymptomatic HIV+ individuals as compared with healthy controls, and further found that CD38 ABC was elevated approximately 2-fold on CD8+DR+ cells as compared with CD8+DR- cells in healthy controls, and almost 2-fold further elevated on CD8+DR+ cells in HIV+ individuals compared with CD8+DR+ cells in healthy controls. In agreement with previous studies, we found increased serum CD8 levels (sCD8) and increased CD8+DR+ counts in asymptomatic HIV+ individuals. However, when sCD8 was expressed relative to CD8+DR+ cell counts (RsCD8), this index was found to be significantly decreased in HIV+ individuals. Although CD38 ABC on CD8+DR+ cells showed no correlation with sCD8, it was significantly correlated with RsCD8 in both HIV+ and HIV- individuals. Absolute lymphocyte counts were strongly correlated with both CD38 ABC and RsCD8 in HIV+ individuals. However, CD4 counts were correlated with CD38 ABC (but not RsCD8) in HIV+ patients and with RsCD8 (but not CD38 ABC) in HIV-controls. Our results suggest that QFCM is significant in understanding the role of CD8+DR+CD38+ cells in processes such as lymphocyte homeostasis and HIV-induced CD4-cell depletion.
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PMID:Indicators of T-cell activation: correlation between quantitative CD38 expression and soluble CD8 levels in asymptomatic HIV+ individuals and healthy controls. 977 71

For some membrane-associated antigens, the number of molecules expressed per cell carries information about the cell's differentiation and activation state. Quantitating antigen expression by flow cytometry has immediate application in monitoring CD38 expression on CD8+ T cells in human immunodeficiency virus 1-associated disease, where elevated CD38 antigen expression is a marker of CD8+ T-cell activation and a poor prognostic indicator. Reproducible methods are needed in order to quantify such antigens. Here we describe a reproducible method for quantitative fluorescence cytometry (QFCM) that depends on the tightly regulated expression of CD4 antigen on human CD4+ T lymphocytes, which we estimated in a study of 57 normal donors to have an interperson coefficient of variation of 4.9%. Using phycoerythrin (PE)-conjugated CD4 monoclonal antibody (mAb) with a nominal fluorochrome to protein ratio of 1:1 and a nominal published value of approximately 50,000 CD4 antibody molecules bound per CD4+ T lymphocyte, we estimated the number of PE molecules detected per relative fluorescence intensity (RFI) unit on our flow cytometer to be 41 (19, 20). This value is called the "RFI multiplier." To estimate the number of CD38 antibodies bound per CD8+ T cell (CD38-ABC) on patient samples, we multiply the measured CD38 RFI value of CD38 staining using a nominal 1:1 conjugate of CD38-PE by the "RFI multiplier." The measurements for CD4 and CD38 were stable for 2 years despite the use of different mAb lots and the potential for drift in instrumentation. We used this approach in a study of nine flow cytometers in which the interinstrument interlaboratory coefficients of variation for CD3-ABC ranged from 3.3% to 5.8% and those for CD38-ABC ranged from 9.8% to 13.8%. These data indicate that CD4 expression can serve as a biological calibrator to standardize fluorescence intensity measurements in longitudinal and multicenter studies.
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PMID:Quantitation of CD38 activation antigen expression on CD8+ T cells in HIV-1 infection using CD4 expression on CD4+ T lymphocytes as a biological calibrator. 977 72

The human immunodeficiency virus type 1 (HIV-1) protease inhibitors (PIs)-saquinavir, ritonavir, nelfinavir, and indinavir-interact with the ABC-type multidrug transporter proteins MDR1 and MRP1 in CEM T-lymphocytic cell lines. Calcein fluorescence was significantly enhanced in MDR1(+) CEM/VBL100 and MRP1(+) CEM/VM-1-5 cells incubated in the presence of various HIV PIs and calcein acetoxymethyl ester. HIV PIs also enhanced the cytotoxic activity of doxorubicin, a known substrate for MDR1 and MRP1, in both VBL100 and VM-1-5 CEM lines. Saquinavir, ritonavir, and nelfinavir enhanced doxorubicin toxicity in CEM/VBL100 cells by approximately three- to sevenfold. Saquinavir and ritonavir also enhanced doxorubicin toxicity in CEM/VM-1-5 cells. HIV-1 replication was effectively inhibited by the various PIs in all of the cell lines, and the 90% inhibitory concentration for a given compound was comparable between the different cell types. Therefore, overexpression of MDR1 or MRP1 by T lymphocytes is not likely to limit the antiviral efficacy of HIV PI therapy.
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PMID:Human immunodeficiency virus protease inhibitors serve as substrates for multidrug transporter proteins MDR1 and MRP1 but retain antiviral efficacy in cell lines expressing these transporters. 1073 63

This open-label, multicenter, single-arm clinical trial assessed the 48-week efficacy of a twice-daily triple nucleoside reverse-transcriptase inhibitor regimen containing a lamivudine (150 mg)-zidovudine (300 mg) combination tablet (COM) and abacavir (ABC; 300 mg) in 87 antiretroviral therapy-experienced, protease inhibitor-naive patients infected with human immunodeficiency virus type 1 (HIV-1). At baseline, the median plasma HIV-1 RNA level was 3.10 log(10) copies/mL, and the median CD4 cell count was 506 cells/mm(3). An intent-to-treat&rcolon;observed analysis showed that, at weeks 24 and 48 of treatment, HIV-1 RNA level was <400 copies/mL in 48 (76%) of 63 and 45 (82%) of 55 patients, respectively, and <50 copies/mL in 37 (59%) of 63 and 31 (56%) of 55 patients, respectively. Previous zidovudine or lamivudine use and presence at baseline of the M184V reverse-transcriptase mutation did not impact virologic response. Median CD4 cell counts were maintained above baseline throughout the study. COM plus ABC was generally well tolerated.
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PMID:Twice-daily triple nucleoside intensification treatment with lamivudine-zidovudine plus abacavir sustains suppression of human immunodeficiency virus type 1: results of the TARGET Study. 1117 Sep 82

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

The anti-human immunodeficiency virus (HIV) activity of abacavir (ABC; 1-(1S,4R)-4-[2-amino-6-(cyclopropylamino)-9H-purin-9-yl]-2-cyclopentene-1-methanol) could be markedly enhanced by administering the aryloxymethoxyalaninyl phosphoramidate prodrug derivative of ABC (pro-ABC-MP) to virus-infected cell cultures. Metabolic studies with radiolabeled ABC and pro-ABC-MP in human T-lymphocyte and primary macrophage cell cultures revealed a significantly increased delivery of the activated (phosphorylated) metabolite of ABC (ABC-MP) by pro-ABC-MP, and the concomittant appearance of markedly higher intracellular levels of carbovir 5'-triphosphate (CBV-TP), which represents the eventual antivirally active metabolite of ABC. The intracellular amounts of ABC-MP and appearance of CBV-TP closely correlated with the extracellular pro-ABC-MP concentrations that were administered to the cell cultures within a concentration range between 0.5 and 100 microM. The highest amounts of CBV-TP were observed within 6-24 h after drug administration. The improved delivery of ABC-MP and metabolic conversion to CBV-TP explain the markedly enhanced antiviral activity of the prodrug of ABC, and warrant further exploration of this prodrug technology on ABC and related compounds to further enhance and optimize their antiviral efficacy.
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PMID:Improved antiviral activity of the aryloxymethoxyalaninyl phosphoramidate (APA) prodrug of abacavir (ABC) is due to the formation of markedly increased carbovir 5'-triphosphate metabolite levels. 1532 72

Multilocus sequence typing (MLST) was used to characterize the genetic profiles of 51 Candida albicans isolates collected from 12 hospitals in Taiwan. Among the 51 isolates, 16 were epidemiologically unrelated, 28 were isolates from 11 critically ill, human immunodeficiency virus (HIV)-negative patients, and 7 were long-term serial isolates from 3 HIV-positive patients. Internal regions of seven housekeeping genes were sequenced. A total of 83 polymorphic nucleotide sites were identified. Ten to 20 different genotypes were observed at the different loci, resulting, when combined, in 45 unique genotype combinations or diploid sequence types (DSTs). Thirty (36.1%) of the 83 individual changes were synonymous and 53 (63.9%) were nonsynonymous. Due to the diploid nature of C. albicans, MLST was more discriminatory than the pulsed-field gel electrophoresis-BssHII-restricted fragment method in discriminating epidemiologically related strains. MLST is able to trace the microevolution over time of C. albicans isolates in the same patient. All but one of the DSTs of our Taiwanese strain collections were novel to the internet C. albicans DST database (http://test1.mlst.net/). The DSTs of C. albicans in Taiwan were analyzed together with those of the reference strains and of the strains from the United Kingdom and United States by unweighted-pair group method using average linkages and minimum spanning tree. Our result showed that the DNA type of each isolate was patient specific and associated with ABC type and decade of isolation but not associated with mating type, anatomical source of isolation, hospital origin, or fluconazole resistance patterns.
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PMID:Multilocus sequence typing for analyses of clonality of Candida albicans strains in Taiwan. 1675 17


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