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)

To investigate whether human immunodeficiency virus type 1 pol gene mutations are selected during prolonged 2',3'-dideoxycytidine (ddC) therapy, we used the polymerase chain reaction to amplify a portion of the reverse transcriptase segment of the pol gene from the peripheral blood mononuclear cell DNA of a patient with AIDS before and after an 80-week course of ddC therapy. The consensus sequence from the second sample contained a unique double mutation (ACT to GAT) in the codon for reverse transcriptase amino acid 69, causing substitution of aspartic acid (Asp) for the wild-type threonine (Thr). A mutation (ACA to ATA) also occurred in the codon for position 165, causing substitution of isoleucine (Ile) for Thr. The GAT (Asp) codon was introduced into the pol gene of a molecular clone of human immunodeficiency virus via site-directed mutagenesis. Following transfection, mutant and wild-type viruses were tested for susceptibility to ddC by a plaque reduction assay. The mutant virus was fivefold less susceptible to ddC than the wild type; cross-resistance to 3'-azido-3'-deoxythymidine or 2'3'-dideoxyinosine was not found. The Ile-165 mutation did not confer additional ddC resistance. The Asp-69 substitution may have contributed to the generation of resistant virus in this patient.
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PMID:Human immunodeficiency virus type 1 pol gene mutations which cause decreased susceptibility to 2',3'-dideoxycytidine. 131 43

Since the first controlled clinical trial of zidovudine (ACT) was terminated in the fall of 1986, much has been learned concerning the use of this agent in the treatment of human immunodeficiency virus (HIV) infection. The recent report of HIV resistance associated with long-term AZT therapy has accelerated the sense of urgency about the development of additional agents for use--either alone or in combination with AZT--against this infection. Several new agents are in various stages of preclinical or clinical evaluation. Some, such as dideoxycytidine, dideoxyinosine, dideoxydidehydrothymidine, azidouridine, and foscarnet, inhibit viral DNA synthesis through inhibition of reverse transcriptase. Other potentially useful agents presumably act at different stages of infection. Soluble CD4, for example, is a soluble form of the receptor to which HIV must bind to infect cells, and castanospermine represents a new class of compounds that block the maturation process of the viral glycoprotein. An apparently more potent and less toxic analogue of the latter agent, N-butyl-deoxynojirimycin, is currently in phase I testing.
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PMID:New antiretroviral agents in the clinic. 223 36

Phenotypes of the tumor cells of malignant histiocytosis (MH) were studied by using monoclonal and polyclonal antibodies in 18 autopsy cases. The tumor cells expressed different antigens in various degrees. Almost all tumor cells showed positive reaction for alpha 1-ACT; partially for alpha 1-AT, LCA and a few for lysozyme as well as LeuM1. It was most likely that the tumor cells of MH originated from the mononuclear phagocytic system (MPS). In order to reveal the relationship between MH and immunodeficiency, morphological changes of the lympho-reticular system in 18 cases of MH were studied. It was found that the lymphoid tissues, including lymph nodes, thymus, tonsil, spleen, bone marrow, lymphoid tissues of GI tract and lung etc showed severe depletion. These findings indicate that MH usually combine with immunodeficiency which is also closely related to the pathogenesis and pathological changes of MH.
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PMID:[Malignant histiocytosis and immunodeficiency]. 258 56

We generated variants of the human immunodeficiency virus type 1 (HIV-1) that are resistant to 2',3'-dideoxycytidine (ddC) and 2',3'-didehydro-3'-deoxythymidine (d4T) by in vitro selection in MT-4 cells. Portions of flanking protease and integrase sequences as well as the complete reverse transcriptase (RT) open-reading frame of these viruses were cloned and sequenced, using polymerase chain reaction (PCR)-based methods. Mutations were observed at amino acid position 65 (Lys-->Arg; AAA-->AGA) when ddC was employed in the selection procedure and at site 50 (Ile-->Thr; ATT-->ACT) when d4T was used. We confirmed the ability of these mutations to confer diminished sensitivity for these compounds by site-directed mutagenesis, in which these mutations were inserted into the pol gene of infectious recombinant HXB2-D DNA. Viruses that contained the site 65 mutation possessed approximately 5-10 fold resistance against ddC when compared with wild-type HXB2-D. The site 50 mutation conferred approximately 30-fold resistance to d4T in these same assays. Similar results were obtained using primary cord blood lymphocytes in drug resistance assays, indicating that these mutations could confer drug resistance in more than one cell type and that the respective mutations could be expressed in cells of primary origin. No cross-resistance against 3'-azido-3'-deoxythymidine (AZT) was noted for either the site 65 or 50 mutations.
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PMID:Identification of novel mutations that confer drug resistance in the human immunodeficiency virus polymerase gene. 751 78

Variable regions with sequence length variation in the human immunodeficiency virus type 1 envelope exhibit an unusual pattern of codon usage with AAT, ACT, and AGT together composing > 70% of all codons used. We postulate that this distribution is caused by insertion of AAT triplets followed by point mutations and selection. Accumulation of the encoded amino acids (asparagine, serine, and threonine) leads to the creation of new N-linked glycosylation sites, which helps the virus to escape from the immune pressure exerted by virus-neutralizing antibodies.
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PMID:Insertion of N-linked glycosylation sites in the variable regions of the human immunodeficiency virus type 1 surface glycoprotein through AAT triplet reiteration. 793 44

Upon prolonged treatment with various antiretroviral nucleoside analogs such as 3'-azido-3'-deoxythymidine, 2',3'-dideoxyinosine, 2',3'-dideoxycytidine, (-)- beta-L-2', 3'dideoxy-3'thiacytidine and 2',3'-didehydro-3'-deoxythymidine, selection of human immunodeficiency virus type 1 (HIV-1) strains with mutations in the reverse transcriptase (RT) gene has been reported. We designed a reverse hybridization line probe assay (LiPA) for the rapid and simultaneous characterization of the following variations in the RT gene: M41 or L41; T69, N69, A69, or D69; K70 or R70; L74 or V74; V75 or T75; M184, I184, or V184; T215, Y215, or F215; and K219, Q219, or E219. Nucleotide polymorphisms for codon L41 (TTG or CTG), T69 (ACT or ACA), V75 (GTA or GTG), T215 (ACC or ACT), and Y215 (TAC or TAT) could be detected. In addition to the codons mentioned above, several third-letter polymorphisms in the direct vicinity of the target codons (E40, E42, K43, K73, D76, Q182, Y183, D185, G213, F214, and L214) were found, and specific probes were selected. In total, 48 probes were designed and applied to the LiPA test strips and optimized with a well-characterized and representative reference panel. Plasma samples from 358 HIV-infected patients were analyzed with all 48 probes. The amino acid profiles could be deduced by LiPA hybridization in an average of 92.7% of the samples for each individual codon. When combined with changes in viral load and CD4+ T-cell count, this LiPA approach proved to be useful in studying genetic resistance in follow-up samples from antiretroviral agent-treated HIV-1-infected individuals.
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PMID:Line probe assay for rapid detection of drug-selected mutations in the human immunodeficiency virus type 1 reverse transcriptase gene. 902 Nov 81

Human immunodeficiency virus (HIV) infection affects body composition, but their relationship has not been studied in pregnant women. We conducted a cross-sectional study among 1669 women receiving antenatal care between 22 and 35 wk of gestation in Harare, Zimbabwe. The role of HIV-1 status and viral load, malaria and elevated serum alpha(1)-antichymotrypsin (ACT, an acute phase protein) in weight, body mass index (BMI), arm circumference (AC), triceps skinfold thickness (TSF), and arm muscle (AMA) and fat (AFA) area were assessed using multiple linear regression analysis. The mean (range) age was 24.4 (14-45) y and gestational age 29 (22-35) wk. HIV infection was present in 31.5% of the women, malaria parasitemia in 0.4% and 11.4% had serum ACT >0.4 g/L. There was no difference in any anthropometric variable between HIV-infected and uninfected women. However, women with viral loads (genome equivalents/mL) between 4 and 5 and >5 log(10) had 1.1 [95% confidence interval (CI): -0.3, 2.3] and 2.5 (95% CI: 0.1, 5.1) kg lower weights compared with uninfected women; this was explained by losses of both AFA and AMA. Malaria parasitemia was associated with 6 cm(2) (95% CI: 0.4; 11.8) or 25% lower AMA. Elevated serum ACT was a negative predictor of all anthropometric variables, i.e., levels between 0.3 and 0.4, 0.4 and 0.5 and >0.5 g/L were associated with 1, 2 and 6 kg lower mean body weights, respectively. Despite the limitations of a cross-sectional design, we conclude that arm fat and muscle areas, reflecting body fat and lean body mass, seem to be unaffected in the majority of HIV-infected pregnant women, but decline with increasing viral loads. The effects of viral load are not explained by elevated serum ACT, which is a strong independent predictor of all anthropometric variables.
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PMID:HIV-1 viral load and elevated serum alpha(1)-antichymotrypsin are independent predictors of body composition in pregnant Zimbabwean women. 1246 18

We have compared nucleotide substitutions and polymorphisms at codons known to confer drug resistance in subtype B strains of human immunodeficiency virus type 1 (HIV-1) with similar substitutions in viruses of other subtypes. Genotypic analysis was performed on viruses from untreated individuals. Nucleotide and amino acid diversity at resistance sites was compared with a consensus subtype B reference virus. Among patients with non-subtype B infections, polymorphisms relative to subtype B were observed at codon 10 in protease (PR). These included silent substitutions (CTC-->CTT, CTA, TTA) and an amino acid mutation, L10I. Subtype A viruses possessed a V179I substitution in reverse transcriptase (RT). Subtype G viruses were identified by silent substitutions at codon 181 in RT (TAT-->TAC). Similarly, subtype A/G viruses were identified by a substitution at position 67 in RT (GAC-->GAT). Subtype C was distinguished by silent substitutions at codons 106 (GTA-->GTG) and 219 (AAA-->AAG) in RT and codon 48 (GGG-->GGA) in PR. Variations relative to subtype B were seen at RT position 215 (ACC-->ACT) for subtypes A and A/E. These substitutions and polymorphisms reflect different patterns of codon usage among viruses of different subtypes. However, the existence of different subtypes may only rarely affect patterns of drug resistance-associated mutations.
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PMID:Nucleotide and amino acid polymorphisms at drug resistance sites in non-B-subtype variants of human immunodeficiency virus type 1. 1527 11

Tuberculosis (TB) is still a major public health problem, compounded by the human immunodeficiency virus (HIV)-TB co-infection and recent emergence of multidrug-resistant (MDR) and extensively drug resistant (XDR)-TB. In this context, aspartokinase of mycobacterium tuberculosis has drawn attention for designing novel anti-TB drugs. Asp kinase is an enzyme responsible for the synthesis of 4-phospho-L-aspartate from L-aspartate and involved in the branched biosynthetic pathway leading to the synthesis of amino acids lysine, threonine, methionine and isoleucine. An intermediate of lysine biosynthetic branch, mesodiaminopimelate is also a component of the peptidoglycan which is a component of bacterial cell wall. To interfere with the production of all these amino acids and cell wall, it is possible to inhibit Asp kinase activity. This can be achieved using Asp kinase inhibitors. In order to design novel Asp kinase inhibitors as effective anti-TB drugs, it is necessary to have an understanding of the binding sites of Asp kinase. As no crystal structure of the enzyme has yet been published, we built a homology model of Asp kinase using the crystallized Asp kinase from M. Jannaschii, as template structures (2HMF and 3C1M). After the molecular dynamics refinement, the optimized homology model was assessed as a reliable structure by PROCHECK, ERRAT, WHAT-IF, PROSA2003 and VERIFY-3D. The results of molecular docking studies with natural substrates, products and feedback inhibitors are in agreement with the published data and showed that ACT domain plays an important role in binding to ligands. Based on the docking conformations, pharmacophore model can be developed by probing the common features of ligands. By analyzing the results, ACT domain architecture, certain key residues that are responsible for binding to feedback inhibitors and natural substrates were identified. This would be very helpful in understanding the blockade mechanism of Asp kinase and providing insights into rational design of novel Asp kinase inhibitors for M.tuberculosis.
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PMID:Exploring the molecular basis for selective binding of Mycobacterium tuberculosis Asp kinase toward its natural substrates and feedback inhibitors: a docking and molecular dynamics study. 2014 Apr 71

Prevalence of Anaplasma, Ehrlichia, Neorickettsia, and Wolbachia DNA in blood of 479 cats collected in different veterinary clinics in Southern Germany was determined using a previously published conventional PCR using 16S-23S intergenic spacer primers (5' CTG GGG ACT ACG GTC GCA AGA C 3' - forward; 5' CTC CAG TTT ATC ACT GGA AGT T 3' - reverse). Purified amplicons were sequenced to confirm genus and species. Associations between rickettsial infections, and feline immunodeficiency virus (FIV), as well as feline leukemia virus (FeLV) status were evaluated. Rickettsial prevalence was 0.4% (2/479; CI: 0.01-1.62%). In the two infected cats, Anaplasma phagocytophilum DNA was amplified. These cats came from different environment and had outdoor access. Both were ill with many of their problems likely related to other diseases. However, one cat had neutrophilia with left shift and the other thrombocytopenia potentially caused by their A. phagocytophilum infection. There was no significant difference in the FIV and FeLV status between A. phagocytophilum-negative and -positive cats. A. phagocytophilum can cause infection in cats in Southern Germany, and appropriate tick control is recommended.
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PMID:Prevalence of selected rickettsial infections in cats in Southern Germany. 2638 62


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