UMLS:C0019693 - FACTA Search

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Query: UMLS:C0019693 (HIV)
170,526 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The HIV-1 nucleocapsid protein, NCp7, is characterized by two CCHC zinc finger motifs which have been shown to stoichiometrically bind zinc in mature virions. Moreover, this binding of zinc proves to be critical in various NCp7 functions, especially in the encapsidation process. To further understand the central role of zinc binding to NCp7, we closely investigated the zinc binding properties of NCp7 and various deleted or substituted derivatives. To this end, the fluorescence of wither the naturally occurring Trp37 or the conservatively substituted Trp16 was used to monitor the binding of zinc to the N- and C-terminal finger motifs, respectively. At pH 7.5, the NCp7 proximal motif was found to bind zinc strongly with 2.8 x 10(14) M-1 binding constant about five times higher than the NCp7 distal motif. Moreover, the binding of zinc to one finger motif decreased the affinity of the second one, and this negative cooperativity was shown to be related to the spatial proximity of the zinc-saturated finger motifs. The binding seemed to be almost equally driven by entropy and enthalpy, and the binding information was essentially encoded by the finger motifs themselves whereas the other parts of the protein only played a marginal stabilization role. As expected, the Cys and His residues of the CCHC motifs were critical and competition between protons and zinc ions to these residues induced a steep pH-dependence of the zinc binding constants to both sites. Taken together, our data provide further evidence for the nonequivalence of the two NCp7 finger motifs.
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PMID:Zinc binding to the HIV-1 nucleocapsid protein: a thermodynamic investigation by fluorescence spectroscopy. 861 1

A new class of very potent and selective non-nucleoside inhibitors of HIV reverse transcriptase (RT) has recently been identified. The prototype compound trovirdine (LY 300046 HCl) and one analogue, MSC-127, have been studied with respect to inhibition of wild-type HIV-1 RT and RT with various mutations known to give rise to resistance to other non-nucleoside RT inhibitors, namely Leu100-->Ile (Ile100), Glu138-->Arg (Arg138), Tyr181-->Cys (Cys181) and Tyr188-->His (His188). The inhibition of HIV-1 RT by trovirdine and MSC-127 was reversible and template dependent. Trovirdine inhibited HIV-1 RT with an IC50 of 0.007 microM when employing heteropolymeric primer/template (oligo-DNA/ribosomal RNA) and dGTP as substrate. Enzyme kinetic studies showed that inhibition of RT by trovirdine was non-competitive with regard to deoxynucleoside triphosphates and uncompetitive with respect to varied primer/template under steady-state conditions. The amino acid changes Leu100, Tyr181 and Tyr188 gave rise to 25-, 147- and 12-fold decrease in inhibition by trovirdine. Enzyme-kinetic studies on trovirdine have been carried out using various RT mutants and compared to the properties of the earlier reported non-nucleoside RT inhibitors 9-Cl-TIBO, nevirapine and L-697,661.
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PMID:Inhibition of human immunodeficiency virus type 1 wild-type and mutant reverse transcriptases by the phenyl ethyl thiazolyl thiourea derivatives trovirdine and MSC-127. 866 92

A case is 48 years-old Japanese man who had a history of frequent sexual contact with prostitutes in Thailand and the Philippines. He presented with chief complaint of chest discomfort in April 1995. His chest X-ray film showed right mediastinal lymph node swelling in other hospital and the sputum smear was strongly positive for acid fast bacilli. In May 1995, he was admitted to our hospital and serological tests for HIV were positive both by EIA and Western blot methods. The CD4 lymphocyte count was 167/microliters. He was diagnosed as a case of AIDS according to the criteria proposed by the AIDS surveillance committee of the Japanese Ministry of Health and Welfare. Although numerous tubercule bacilli were detected in sputum, the chest X-ray did not show abnormal shadow in lung fields. So the diagnosis of bronchial tuberculosis was suspected by these apparently contradictory findings and the bronchoscopy was performed. Biopsy specimen of the bronchial mucous membrane obtained by bronchoscopy confirmed the presence of acid fast bacilli by Ziehl-Neelsen's staining method, however, histological findings were atypical of tuberculosis. A month after the initiation of treatment with isoniazid, rifampicin and ethambutol and AZT, his clinical symptoms improved and the sputum smear and the culture tests for tubercule bacilli converted to negative. Complications of AIDS, (Pneumocystis carinii infection, Cytomegalo virus infection, Kaposi's sarcoma, etc) other than tuberculosis have not developed to date. In the past reports, we could not find reports of bronchial tuberculosis with AIDS. Tuberculous granuloma formation was scarce in this case, and it was suspected that bronchial tuberculosis with AIDS would show characteristic sign as same as pulmonary tuberculosis with AIDS.
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PMID:[A case of AIDS with bronchial tuberculosis]. 867 92

The most frequent neurological complication of AIDS is a dementia-like syndrome. Power and collaborators (J Virol 1994; 68:4643-4649) have reported an association between the clinical signs of AIDS dementia and the amino acid composition of two positions (305 and 329) within the V3 region of HIV-1 strains amplified from brain tissue. Similarly, we analyzed position 305 in the V3 region of HIV-1 present in the brain or cerebrospinal fluid of 25 nondemented subjects at different clinical stages of HIV-1 infection. Our results are, however, at variance with the findings presented by Power and colleagues. Histidine, found to be common among sequences derived from demented patients, was also present in the majority (16 of 25) of nondemented patients analyzed by us. In the hands of Power and colleagues, sequences derived from nondemented patients contained proline at position 305. None of our patients had proline in this position. We also asked the question whether the presence of a specific amino acid at position 305 of the V3 loop is linked to an increased capacity of HIV-1 isolates to infect primary microglial cells, the major target cell for HIV-1 infection in the brain. Primary HIV-1 isolates derived from blood and cerebrospinal fluid of five patients, two asymptomatic and three AIDS patients, were used to infect microglia cell cultures. Infection was monitored by syncytium formation and by p24 antigen release in the culture supernatant. All but one of the paired blood/CSF isolates replicated in human brain cultures. Replication occurred independently from the amino acid present at position 305 of the V3 region of the viral envelope. Our results indicate that the majority of HIV-1 isolates, even derived during the asymptomatic stage, have the capacity to infect microglial cells. The relevance of viral envelope sequences in determining tropism for microglial cells and development of neurological symptoms remains an open question.
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PMID:HIV type 1 V3 sequences and the development of dementia during AIDS. 867 1

A nosocomial outbreak of scabies in a specialist inpatient HIV unit resulted from a patient admitted with crusted scabies. Treatment of his infestation with topical scabicides alone failed and he remained infectious for several weeks. His infestation was then eradicated with combined topical treatment and oral ivermectin. In total, 14 (88%) out of 19 ward staff became symptomatic, and 4 (21%) had evidence of scabies on potassium hydroxide examination of skin scrapings. The ward infection control policy was changed to distinguish patients with crusted scabies from those with ordinary scabies. A second patient with crusted scabies was treated with combined oral and topical therapy early in his admission and nursed with more stringent isolation procedures. No nosocomial transmission occurred and his infestation responded rapidly to treatment. Patients with crusted scabies require strict barrier nursing if nosocomial transmission is to be avoided. Ivermectin combined with topical scabicides may be a more efficacious treatment than topical scabicides alone in such patients.
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PMID:Crusted ("Norwegian") scabies in a specialist HIV unit: successful use of ivermectin and failure to prevent nosocomial transmission. 903 54

The Cys-Xaa2-Cys-Xaa4-His-Xaa4-Cys zinc fingers of retroviral nucleocapsid proteins are prime antiviral targets because of conservation of the Cys and His chelating residues and the absolute requirement of these fingers in both early and late phases of retroviral replication. We previously reported that certain disulfide-substituted benzamides (DIBAs) chemically modify the Cys residues of the fingers, resulting in inhibition of human immunodeficiency virus type 1 (HIV-1) replication (W. G. Rice, J. G. Supko, L. Malspeis, R. W. Buckheit, Jr., D. Clanton, M. Bu, L. Graham, C. A. Schaeffer, J. A. Turpin, J. Domagala, R. Gogliotti, J. P. Bader, S. M. Halliday, L. Coren, R. C. Sowder II, L. O. Arthur, and L. E. Henderson, Science 270:1194-1197, 1995). We now examine the consequences of the interaction of DIBAs with the zinc fingers of the HIV-1 p7 nucleocapsid protein and its Pr55gag precursor. In HIV-1-infected U1 cells, DIBAs inhibited the release of infectious virions, and even under conditions in which virion particles were produced, the particles were noninfectious. DIBAs caused abnormal processing of Gag precursors, and the inhibitory effect on processing was not due to inhibition of the HIV-1 protease enzyme or Pr55gag myristoylation. Rather, the defect in processing was due to the formation of intermolecular cross-linkages among the zinc fingers of adjacent Gag molecules, rendering the precursors no longer recognizable by HIV-1 protease. Likewise, DIBAs caused intermolecular cross-linkage among recombinant Pr55gag packaged into pseudovirions, thereby generating modified precursors that were resistant to the action of protease. Thus, DIBAs chemically modified the mutationally intolerant retroviral zinc fingers in infected cells, interrupting protease-mediated maturation of virions and leading ultimately to the production of compromised virions.
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PMID:Inhibitors of human immunodeficiency virus type 1 zinc fingers prevent normal processing of gag precursors and result in the release of noninfectious virus particles. 870 44

A 25-year-old man with hemophilia A who had received concentrated plasma and plasma factor VIII products since childhood presented with a productive cough and a fever. The CD4/CD8 ratio of peripheral lymphocyte subsets was very low and the serum was positive for anti-HIV antibodies. The chest roentgenogram showed bilateral multiple nodules with cavity formation. The patient underwent transbronchial lung biopsy, and the specimen obtained had Pneumocystic carinii organisms. The patient was treated with sulfamethoxazole and trimethoprim compounds, and with inhaled pentamizine. His condition improved. Patients with pulmonary pneumocystosis usually present with interstitial infiltrates spreading from the hilium to the periphery of the lungs, and nodular and cavitary lesions are unusual pulmonary radiographic findings in this condition.
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PMID:[Nodular and cavitary pneumocystosis in a patient with hemophilia A and the acquired immunodeficiency syndrome]. 871 4

The nucleocapsid (NC) protein of HIV-2 (NCp8) contains two Cys-His arrays which function as zinc finger motifs (ZFMs). In this study, we analyzed the viral RNA-binding properties of NCp8-derived synthetic peptides using ultraviolet (UV) cross-linking assay. Several synthetic peptides containing ZFM(s) interacted pH-dependently with in vitro-synthesized HIV-2 RNA. Although the peptides corresponding to the 1st and 2nd ZFMs, respectively, failed to interact with the viral RNA, the corresponding peptides flanked by basic amino acid clusters interacted tightly. Furthermore, basic amino acid residues within a cluster adjacent to ZFMs contributed to the RNA-binding of NCp8 more than Cys and His residues within the ZFM in vitro. In competitive UV cross-linking assay using non-specific RNA as a competitor, the peptides corresponding to the 1st and 2nd ZFMs flanked by basic amino acid clusters interacted specifically with viral RNA. These findings suggest that both ZFM regions of HIV-2 may be concerned with the specificity of packaging of genomic viral RNA into the virion.
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PMID:Viral RNA binding properties of human immunodeficiency virus type-2 (HIV-2) nucleocapsid protein-derived synthetic peptides. 873 36

All retroviral nucleocapsid (NC) proteins, except those of spumaretroviruses, contain one or two copies of the conserved sequence motif C-X2-C-X4-H-X4-C. The conserved cysteine and histidine residues coordinate a zinc ion in each such motif. Rice et al. (W. G. Rice, J. G. Supko, L. Malspeis, R. W. Buckheit, Jr., D. Clanton, M. Bu, L. Graham, C. A. Schaeffer, J. A. Turpin, J. Domagala, R. Gogliotti, J. P. Bader, S. M. Halliday, L. Coren, R. C. Sowder II, L. 0. Arthur, and L. E. Henderson, Science 270:1194-1197, 1995) have described a series of compounds which inactivate human immunodeficiency virus type 1 (HIV-1) particles and oxidize the cysteine thiolates in the NC zinc finger. We have characterized the effects of three such compounds on Moloney murine leukemia virus (MuLV). We find that, as with HIV-1, the compounds inactivate cell-free MuLV particles and induce disulfide cross-linking of NC in these particles. The killed MuLV particles were found to be incapable of synthesizing full-length viral DNA upon infection of a new host cell. When MuLV particles are synthesized in the presence of one of these compounds, the normal maturational cleavage of the Gag polyprotein does not occur. The compounds have no effect on the infectivity of human foamy virus, a spumaretrovirus lacking zinc fingers in its NC protein. The resistance of foamy virus supports the hypothesis that the zinc fingers are the targets for inactivation of MuLV and HIV- I by the compounds. The absolute conservation of the zinc finger motif among oncoretroviruses and lentiviruses and the lethality of all known mutations altering the zinc-binding residues suggest that only the normal, wild-type structure can efficiently perform all of its functions. This possibility would make the zinc finger an ideal target for antiretroviral agents.
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PMID:Inactivation of murine leukemia virus by compounds that react with the zinc finger in the viral nucleocapsid protein. 876 2

A series of pyridobenzothiodiazepindioxides such as the 11-ethyl-6,8,9-trimethyl-6,11-dihydro-pyrido[2,3-f] [2,1,5]benzothiodiazepine-5,5-dioxide and arylpiridodiazepines such as the 6,7-dihydro-7-methyl-12-ethyl-pyrido[2,3-b] pyrido(2',3'-4,5]furo[2,3-f][1,4]diazepin-6(12H)-thio and the 6,7-dihydro-7-methyl-12-ethyl-pyrido[2,3-b]pyrido- [2,3-4,5]thieno[2,3-f][1,4] diazepin-6(12H)-thione were found to inhibit human immunodeficiency virus type 1 [HIV-1(IIIB)] replication at a concentration of 0.003-0.04 microM without being cytotoxic at a 3,000- to 15,000-fold higher concentration. These compounds proved effective against a variety of HIV-1 strains, including those that are resistant to 3'-azido-3' deoxythymidine (AZT), but not against HIV-2, simian immunodeficiency virus or herpes simplex virus. An HIV-1 strain containing the 188 Tyr-->His mutation in the reverse transcriptase displayed severely reduced sensitivity to the compounds. The specificity of these compounds is due to an interaction with the reverse transcription process. The 6,7-dihydro-7-methyl-12-ethyl-pyrido[2,3-b]pyrido [2,3-4,5]thieno[2,3-f][1,4]diazepin-6(12H)-thione (MEN 10979) enhanced the anti-HIV-1 activity of AZT and dideoxyinosine (ddI) in a synergistic manner. The new arylpyrido-diazepine and -thiodiazepine derivatives appear to be drug candidates for the treatment of HIV-1 infection.
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PMID:New arylpyrido-diazepine and -thiodiazepine derivatives are potent and highly selective HIV-1 inhibitors targeted at the reverse transcriptase. 878 3

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