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)

Several previously unnoticed genes in the human immunodeficiency virus type 1 (HIV-1), potentially encoding selenoproteins, have been discovered by analyzing the genomic RNA structure and its relation to novel open reading frames. We have found a number of new potential RNA pseudoknots, including one in the long terminal repeat, several that coincide with highly conserved enzyme active site sequences in the pol coding region, and one in the env coding region. These pseudoknots can potentially direct the synthesis of selenocysteine (SeC) containing--1 frameshift fusion proteins. This is possible because we have found potential SeC insertion sequences (SECIS) in the RNA of HIV and other retroviruses; such structures are known to be necessary and sufficient for the incorporation of SeC at UGA "stop" codons anywhere in a eukaryotic mRNA. In several locations, UGA codons in the -1 reading frame are highly conserved across a broad spectrum of primate immunodeficiency viruses. Due to the degeneracy of the genetic code, this conservation cannot be explained by evolutionary selection of the pol gene protein sequence alone. Such observations, combined with the conservation of the associated reading frames, strongly suggest that these are real genes, and thus that the pseudoknots are also real. A protease pseudoknot-directed -1 frameshift fusion protein contains a highly conserved SeC codon and has significant similarities to a number of DNA binding proteins, including papillomavirus E2 proteins, suggesting it may be a virally encoded repressor of HIV transcription when cleaved by protease from the rest of the gag-pol gene product. A reverse transcriptase (RT) frameshift fusion protein replaces the RT active site with a highly conserved SeC-containing module. An integrase frameshift fusion protein contains the N-terminal integrase DNA-binding domain and a potential ATP-binding "GKS" motif; it has significant similarities to several helicases, but no SeC codons. A potential frameshift fusion protein from env has one SeC codon, but not in a highly conserved position. SeC incorporation could extend the nef gene product by 33 residues through the C-terminal UGA codon without frameshifting, potentially leading to substantial SeC utilization in infected cells.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:A basis for new approaches to the chemotherapy of AIDS: novel genes in HIV-1 potentially encode selenoproteins expressed by ribosomal frameshifting and termination suppression. 806 94

Topoisomerase I activity was detected in detergent-disrupted human immunodeficiency virus type 1 (HIV-1) particles. The enzyme did not require ATP for its conversion of SC DNA to an RC form, had divalent cation requirements similar to those of eukaryotic topoisomerase I, and was significantly inhibited by the specific topoisomerase I inhibitor camptothecin. However, camptothecin failed to inhibit replication of HIV in infected cells at nontoxic concentrations, and an active site motif for topoisomerase I could not be detected on the HIV genome. These results suggests that HIV does not encode a novel topoisomerase I, but rather packages the cellular enzyme.
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PMID:Cellular topoisomerase I activity associated with HIV-1. 814 41

In situ hybridization of human immunodeficiency virus-1 (HIV-1) has been performed on eight eyes from eight distinct acquired immune deficiency syndrome patients (three cases had a normal fundus examination and five presented with cytomegalovirus retinitis). The eyes were removed at autopsy and frozen immediately. Contiguous 10-mu cryostat sections were obtained and tested with a HIV probe labeled by nick-translation with [35S]-ATP. HIV-1 RNA was detected in the retina of two acquired immune deficiency syndrome patients. The first positive case presented with typical ophthalmological and histopathological cytomegalovirus retinitis, the second one was not related to cytomegalovirus, according to clinical or histopathological classical criterias. HIV-1 was localized in retinal vascular walls. This shows that there is an active replication of HIV in retina of some acquired immune deficiency syndrome patients.
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PMID:In situ hybridization of HIV-1 RNA in retinal vascular wall. 823 45

The antiviral activity of the purine dideoxynucleosides 2',3'-dideoxyadenosine (ddA) and 2',3'-dideoxyinosine (ddI) is dependent on their conversion into ddA triphosphate in vivo. 5-Amino-4-imidazolecarboxamide riboside (AICA riboside), a natural metabolite in purine biosynthetic pathways, is converted into IMP, a substrate for the biosynthesis of adenine and guanine nucleotides, and enhances the intracellular purine nucleotide pools. Because IMP also serves as a phosphate donor in the anabolic phosphorylation of ddI (and ddA) into ddI monophosphate by the cytosolic enzyme 5'-nucleotidase, we investigated the effects of AICA riboside on the phosphorylation and antiretroviral activity of these purine nucleoside analogs. At an AICA riboside concentration of 0.5 mM, there was a approximately 2-fold increase in the intracellular ATP and GTP levels, whereas a nearly 8-fold increase was observed for the phosphorylation of ddA (or ddI). A marked reduction in intracellular pools of the pyrimidine nucleotides CTP and UTP was observed in AICA riboside-treated cells and inhibited cell proliferation. However, this growth inhibition was prevented by the addition of uridine to the cultures. Cells pretreated with AICA riboside and ddI were less susceptible to human immunodeficiency virus (HIV) infection and synthesized reduced levels of HIV proviral DNA. A 10-fold potentiation of the effectiveness of ddI against both wild-type HIV (HIVIIIB) and a ddI-resistant variant HIV was observed in the presence of 0.5 mM AICA riboside. These results show that AICA riboside modulates the anabolism and antiviral activity of ddI, and they have implications for possible therapies with dideoxynucleosides.
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PMID:5-Amino-4-imidazolecarboxamide riboside potentiates the metabolism and anti-human immunodeficiency virus activity of 2',3'-dideoxyinosine. 834 Dec 76

The two enantiomers of 2',3'-dideoxy-3'-thiacytidine (BCH-189) and their 5-fluoro analogs (FTC) were found to be good substrates for human 2'-deoxycytidine kinase with Km values in the 5.7 to 42.1 microM range. The affinity of the (-)-enantiomers was greater than that of the (+)-compounds. These results may explain the greater in vitro antiviral potency against human immunodeficiency virus and hepatitis B virus of the (-)-enantiomers when compared to their (+)-counterparts. The (+)- and (-)-enantiomers of FTC and BCH-189 are the first nucleoside analogs for which we have observed lower apparent kinetic constants for this enzyme in the presence of ATP compared to UTP.
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PMID:Affinity of the antiviral enantiomers of oxathiolane cytosine nucleosides for human 2'-deoxycytidine kinase. 838 48

Mycoplasma fermentans and Mycoplasma pirum have been recovered from human immunodeficiency virus (HIV)-positive persons. M. fermentans has been isolated with much higher frequency from HIV-positive than from HIV-negative persons. Mycoplasma genitalium has been detected by polymerase chain reaction in the blood of a patient with AIDS. Little is known about the biology of these mycoplasmas, especially their physiology, biochemistry, and growth response to inhibitors of essential metabolic loci or transport. Metabolically, they resemble other Mycoplasma species. Those studied lack cytochromes, the tricarboxylic acid cycle, and portions of the hexose monophosphate shunt. According to limited data, they fix CO2, use ATP to phosphorylate fructose-6-phosphate, have substrate phosphorylation and transaminase(s), and interconvert most purines and pyrimidines. The synthesis of thymidine may be limited. They may require a variety of essential small molecules for optimal growth (e.g., pyridoxal phosphate, ribose-1-phosphate). Their pathogenic potential and cultural lability may involve the production of the superoxide anion and the hydroxyl radical. We hypothesize that the mycoplasmas generate toxic oxygenated products that damage the host cell, probably membrane, permitting the mycoplasmas to gain easier access to the interior of the cell. The mycoplasma-damaged host cell membrane may also effect the maturation or release of HIV particles from the cell.
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PMID:The metabolism of AIDS-associated mycoplasmas. 839 28

Clathrin is the structural protein of coated membranes involved in receptor-mediated endocytosis and aspects of Golgi sorting in eukaryotic cells. We have now detected a stoichiometric complex of clathrin with a novel protein of M(r) approximately 100,000 (100K) in lysates of different mammalian cells. Formation of the complex, which also includes the 70K heat-shock protein Hsc70, occurs within 15 min of synthesis. The 100K protein has been identified as valosin-containing protein (VCP; ref. 1), an early substrate for tyrosine phosphorylation on T-cell receptor activation. Further, VCP is the mammalian homologue of yeast Cdc48p (ref. 3) and is a member of a larger gene family that includes putative ATP-binding proteins involved in vesicle transport and fusion, 26S proteasome function, regulation of the expression of human immunodeficiency virus, and assembly of peroxisomes. The association with clathrin and the morphological and catalytic similarity to the chaperonin proteins indicate that VCP may modulate protein-protein interactions in membrane transport processes.
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PMID:Valosin-containing protein, VCP, is a ubiquitous clathrin-binding protein. 841 90

Proliferative defects have been reported at the level of DNA synthesis, even in T-lymphocytes from asymptomatic human immunodeficiency virus type-1+ (HIV-1+) patients. Since purine and pyrimidine ribonucleotide availability is crucial for proliferation, we compared the ability of HIV-1- and HIV-1+ T-lymphocytes (> 95% CD4+ and CD8+) to activate de novo biosynthetic and salvage pathways following phytohemagglutinin stimulation using 14C-labeled precursors. The striking abnormality already detectable in asymptomatic patients' cells was the impaired ability of CTP, UDP-Glc, and UTP pools to expand over 72 h (44-70% of control), although ATP and GTP pools and responses were normal. In symptomatic patients, resting T-cells showed markedly reduced pyrimidine pools (53-74% of control) with no change following activation. Relatively normal ATP, GTP, and NAD pools masked the same impaired response of de novo synthesis to activation, with ATP and GTP being reduced by 50% at 48 h. Purine salvage was more active than the control in unstimulated HIV-1+ cells. This impaired de novo synthesis in HIV-1+ T-lymphocytes severely restricts the availability of ribonucleotides for vital growth-related activities such as membrane expansion and strand break repair as well as DNA and RNA synthesis. The data indicate that resting T-lymphocytes from symptomatic patients survive through enhanced salvage, but the stimulation induces metabolic cell death, and provide an explanation for the activation-associated lymphocyte death seen in HIV-1+ T-lymphocytes.
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PMID:T-lymphocytes from AIDS patients are unable to synthesize ribonucleotides de novo in response to mitogenic stimulation. Impaired pyrimidine responses are already evident at early stages of HIV-1 infection. 853 Mar 57

Fastidious mycobacteria usually infect immunocompromised hosts (human immunodeficiency virus-infected or otherwise immunosuppressed patients). We here describe severe lymphadenitis, caused by a fastidious mycobacterium closely related to Mycobacterium genavense, in an apparently immunocompetent woman, whose brother had died from an unidentified mycobacterial infection in 1969. A variety of techniques, including inoculation of nude mice, histopathology, electron microscopy, lipid analysis, ATP measurements, and molecular biology, were used to characterize this mycobacterium. All attempts to culture the etiological agent on many different media failed. The organism multiplied only in congenitally athymic nude mice. Although phenotypically similar to M. genavense, the mycobacterium differs from M. genavense by three nucleotides of the 16S rRNA gene sequence. Various antimycobacterial drugs were administered, including gamma interferon, but multiple relapses occurred. Finally, therapy with a combined regimen of clarithromycin, clofazimine, rifabutin, and ethambutol was curative. To our knowledge, this is the first report of lymphadenitis in an apparently immunocompetent patient, caused by a noncultivable Mycobacterium sp. closely related to M. genavense. This study emphasizes the importance of employing a variety of diagnostic approaches such as the inoculation of laboratory animals, histopathology, electron microscopy, lipid analysis, ATP measurements, and molecular biology to characterize novel microorganisms that cannot be cultured in vitro.
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PMID:Cervical lymphadenitis caused by a fastidious mycobacterium closely related to Mycobacterium genavense in an apparently immunocompetent woman: diagnosis by culture-free microbiological methods. 856 3

We extended our previous study with 3'-azido-3'-deoxythymidine nucleotides [Proc. Natl. Acad. Sci. USA 91:5771-5775 (1994)] and examined the effects on human immunodeficiency virus type 1 (HIV-1) integrase of the nucleotides of three nucleoside analogues currently under evaluation in clinical trials: beta-D-2',3'-didehydro-3'-deoxythymidine, beta-D-2'-ara-fluoro-2', 3'-dideoxyadenosine, and beta-L-2',3'-dideoxy-3'-thiacytidine. Beta-D-2',3'-Didehydro-3'-deoxythymidine and beta-D-2'-ara-fluoro-2',3'-dideoxyadenosine nucleotides had IC50 values for strand transfer of 100 and 200 microM, respectively, whereas the corresponding 2',3'-dideoxynucleoside triphosphates, ddT triphosphate and ddA triphosphate, did not inhibit the integrase at 800 and 200 microM, respectively. Beta-L-2',3'-Dideoxy-3'-thiacytidine triphosphate had no effect up to 500 microM. The L-enantiomers of 5-fluoro-2',3'-dideoxycytidine monophosphate and triphosphate had IC50 values of approximately 40 microM, whereas their D-enantiomer isomers showed no inhibition at 200 microM. NAD, pyridoxal phosphate, and coumermycin A1, which exhibit no antiviral activity but are typically used to probe nucleotide binding sites, were also tested. NAD was inactive, and its etheno derivative exhibited activity at 1 mM. In contrast, pyridoxal phosphate (IC50 = 18 microM and coumermycin A1 (IC50 = 5 microM were potent inhibitors. None of the coumermycin monomeric derivatives were active integrase inhibitors. The physiological ribonucleotides ATP and GTP inhibited HIV-1 integrase at or near cellular concentrations, suggesting that they may regulate HIV-1 integrase activity in cells. In general, the active nucleotides tested inhibited binding of HIV-1 integrase to its substrate DNA an inhibited an integrase deletion mutant containing only amino acids 50-212, indicating that nucleotides bind to the enzyme catalytic core. Consisently, the choice of nucleophile in the 3'-processing reaction was blocked to the same extent regardless of the nucleotide used (water, glycerol, or the viral DNA hydroxyl) by the enzyme. These observations suggest new strategies for antiviral drug development that could be based on nucleotide analogues as inhibitors of HIV-1 integrase.
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PMID:Effects of nucleotide analogues on human immunodeficiency virus type 1 integrase. 860 89


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