Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0019693 (HIV)
 170,526 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Tat, the transactivating protein from HIV, forms a metal-linked dimer with metal ions bridging cysteine-rich regions from each monomer. This novel arrangement is distinct from the "zinc finger" domain observed in other eukaryotic regulatory proteins. Ultraviolet absorption spectra show that Tat binds two Zn2+ or two Cd2+ ions per monomer, and electrophoresis of the Tat-metal complexes demonstrates that the protein forms metal-linked dimers. Partial proteolysis and circular dichroism spectra suggest that metal binding has its primary effects in the cysteine-rich region and relatively little effect on the folding of other regions. These results suggest new directions for biological studies and new approaches to drug design.
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PMID:Tat protein from human immunodeficiency virus forms a metal-linked dimer. 283 44

Serum zinc levels were assayed in patients with AIDS and related syndromes, using spectrophotometry and atomic absorption. Statistical data have shown that serum zinc levels, in addition to being significantly lower (p less than 0.001) among different groups and controls, decrease progressively with the worsening of the clinical and immunological picture from LAS to AIDS. Serum zinc levels in patients with AIDS and ARC have, moreover, been demonstrated to be related (r = 0.8240; p less than 0.001) to the lymphocyte subset CD4 helper-induced. These results suggest that serum zinc determination and possibly zinc therapy might be reasonably considered in the management of patients with symptoms of HIV infection.
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PMID:[Zinc and lymphocyte subsets in patients with HIV infection]. 296 39

Zinc and immune function relationship has been extensively studied. Both in experimentally induced mineral deficit and in genetically determined deficit observable in acrodermatitis enteropathica and in enteropathy of Danish A-46 cattle, a B and T dependent antibody response decrease, a T dependent cytolytic response decrease and a natural killer cytotoxic activity decrease are present noteviously. Serious reduction of the immune function is present, in proportion to the value of low zinc plasmatic level, in elderly patients, in malnourished and seriously zinc deficient children, in patients subjected to total parenteral supply, in HIV infections and especially in evident AIDS: in this condition the plasmatic zinc level can be considered, together with the CD4+ lymphocytes amount and the B2-microglobulin value, a disease progression marker. Zinc immunostimulating action mechanisms are complex, although thymic hormone (of which zinc is essential cofactor) stimulation seems to be most important. Zinc supplementation, also parenterally, can be useful in immunodeficiency (in the elderly, in the post-surgical patients, in genetically determined or alimentary induced deficit, in AIDS.
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PMID:Zinc and immune function. 747 75

Retroviruses are a family of widespread small animal viruses about 110 nm in diameter, composed of an inner core surrounded by an outer envelope formed of a lipid bilayer of cellular origin in which are anchored viral glycoproteins. The inner core is formed by an outer shell of capsid protein molecules (CA protein) surrounding the dimeric RNA genome in close association with about 2000 molecules of nucleocapsid protein (NC protein) and molecules of reverse transcriptase (RT) and integrase (IN). Conversion of the genomic single-stranded RNA into a double-stranded proviral DNA by RT takes place in the nucleocapsid substructure and involves two DNA strand transfers to generate the long terminal repeats (LTR) required for IN-mediated integration of the proviral DNA into the cellular genome and its expression. In this review we have summarized some of the properties and functions of the nucleocapsid protein of the most intensely studied oncoretroviruses (MuLV and ASLV) and lentiviruses (HIV-1). Recent biochemical and genetic data on retroviral NC proteins have shown that this small viral protein endowed with a strong affinity for nucleic acids exhibits nucleic acid annealing and strand transfer activities and is required for the formation of infectious viral particles. These new activities of NC protein are most probably necessary at the early steps of proviral DNA synthesis. The 3-D structures of HIV-1 and MoMuLV NC proteins, deduced from NMR studies, are characterized by a central globular domain with one (MoMuLV) or two (HIV-1) zinc fingers. This should facilitate a rational approach of new anti-HIV therapies based on inhibition of NC protein functions. Due to space limitations and the very abundant literature on retroviruses, references to articles prior to the publication of the second volume of RNA Tumor Viruses in 1985 (Weiss et al., 1985) will be minimal. We also direct the reader to an excellent review which summarizes recent insights into biochemical and structural aspects of the retroviral enzymes PR, RT and IN (Katz & Skalka, 1994).
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PMID:First glimpses at structure-function relationships of the nucleocapsid protein of retroviruses. 750 Mar 30

Strategies for the treatment of human immunodeficiency virus-type 1 (HIV-1) infection must contend with the obstacle of drug resistance. HIV-1 nucleocapsid protein zinc fingers are prime antiviral targets because they are mutationally intolerant and are required both for acute infection and virion assembly. Nontoxic disulfide-substituted benzamides were identified that attack the zinc fingers, inactivate cell-free virions, inhibit acute and chronic infections, and exhibit broad antiretroviral activity. The compounds were highly synergistic with other antiviral agents, and resistant mutants have not been detected. Zinc finger-reactive compounds may offer an anti-HIV strategy that restricts drug-resistance development.
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PMID:Inhibitors of HIV nucleocapsid protein zinc fingers as candidates for the treatment of AIDS. 750 43

The reverse transcriptase (RT) of equine infectious anemia virus (EIAV) shares sequence similarity with the RTs of other lentiviruses, particularly with the RTs of human immunodeficiency viruses types 1 and 2 (HIV-1 and HIV-2, respectively), the causative agents of acquired immunodeficiency syndrome (AIDS). There is a 41-42% sequence identity between EIAV RT and both HIV RTs (which have 61% sequence identity to each other). We have compared the enzymic properties of EIAV RT with those of HIV-1 RT. Several aspects of the activities of EIAV RT differ from the corresponding activities of HIV-1 RT. There are significant differences in the inhibition of the DNA polymerase activities by the deoxynucleoside triphosphate analogs, 3'-azido-2,3'-dideoxythymidine triphosphate, dideoxyTTP and dideoxyGTP and by the nonnucleoside inhibitor, tetrahydroimidazo[4,5,1-jk-1,4]benzodiazepin-2-(1H)-one and thione; in the dependence of DNA polymerase and RNase H activities on pH; in the inhibition of the DNA polymerase activities by the thiol-specific reagent N-ethylmaleimide; in the specific DNA polymerase activity; in the inhibition of the ribonuclease H activity by the zinc chelator orthophenanthroline. However, there are several cases in which EIAV RT and HIV-1 RT are more similar than was previously found for HIV-1 RT and HIV-2 RT. These include the Km values for the DNA polymerase activities, the heat stability of the DNA polymerase functions and the specific activity of the RNase H function.
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PMID:The catalytic properties of the reverse transcriptase of the lentivirus equine infectious anemia virus. 750 81

The inhibition of HIV-1 integrase by flavones and related compounds was investigated biochemically and by means of structure-activity relationships. Purified enzyme and synthetic oligonucleotides were used to assay for three reactions catalysed by integrase: (1) processing of 3' termini by cleavage of the terminal dinucleotide; (2) strand transfer, which models the integration step; and (3) "disintegration," which models the reversal of the strand transfer reaction. Inhibitions of all three reactions by flavones generally occurred in parallel, but caffeic acid phenethyl ester (CAPE) appeared to inhibit reaction 2 selectively. CAPE, however, inhibited reactions 1 and 3 effectively when preincubated with the enzyme, suggesting that this compound differs from the flavones primarily in requiring more time to block the enzyme. The core integrase fragment consisting of amino acids 50-212 retained the ability to catalyse reaction 3, and flavones and CAPE retained the ability to inhibit. Hence, the putative zinc-finger region that is deleted in this fragment is probably not the target of inhibition. Inhibition by flavones usually required the presence of at least one ortho pair of phenolic hydroxyl groups and at least one or two additional hydroxyl groups. Potency was enhanced by the presence of additional hydroxyl groups, especially when present in ortho pairs or in adjacent groups of three. Inhibitory activity was reduced or eliminated by methoxy or glycosidic substitutions or by saturation of the 2,3 double bond. These structure-activity findings for flavones were generally concordant with those previously reported for reverse transcriptase and topoisomerase II. These findings are discussed in the context of a review of the effects of flavones on various enzymes, the possible mechanisms of inhibition, and the potential for building upon a general pharmacophore to generate target specificity.
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PMID:Inhibition of HIV-1 integrase by flavones, caffeic acid phenethyl ester (CAPE) and related compounds. 752 Jun 98

We describe two simple novel procedures, one direct and the other involving hybridization, for the enzyme-linked immunosorbent assay (ELISA)-based detection, quantitation, and validation of polymerase chain reaction (PCR)-amplified DNA. Both procedures are applicable to any PCR reaction, and do not require specially synthesized or enzyme-tagged oligonucleotides. We obtained accurate quantitation of PCR-amplified human cc10kDa cDNA with a sensitivity of about 0.6 fmoles. This cDNA was also used to detect single-base insertions, deletions, and substitutions specifically. Additionally, we could readily distinguish zinc-finger Y chromosome-specific genomic sequences in mixtures of male and female cells and normal and mutant cystic fibrosis transmembrane conductance regulator (CFTR) gene sequences in crude fibroblast lysates. To our knowledge, this is the first report of point mutation detection in solution by ELISA without allele-specific amplification or ligation. These novel procedures have vast potential for basic and clinical applications, including gene expression studies, rapid screening of genetic diseases, detection of oncogene and anti-oncogene mutations, and identification of pathogens (e.g., HIV-1) in clinical specimens.
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PMID:Nonradiometric ELISA-based quantitation and validation of polymerase chain reaction-amplified DNA, including detection of point mutations, without allele-specific amplification, or ligation. 752 25

A number of structurally diverse compounds have been shown to be potent inhibitors of the DNA polymerase activity of human immunodeficiency virus (HIV-1) reverse transcriptase (RT). The compounds can be grouped into two broad classes: nucleoside analogs and nonnucleoside inhibitors. The nonnucleoside inhibitors are quite specific for the polymerase activity of HIV-1 RT; they do not affect the polymerase activity of HIV-2 RT or the ribonuclease H (RNase H) activity of either HIV-1 RT or HIV-2 RT. Structural, biochemical, and genetic analyses showed that this group of inhibitors binds in a hydrophobic pocket near the polymerase active site. Mutations in amino acids that line this hydrophobic pocket, for example at tyrosine 181, tyrosine 188, or lysine 103, lead to enzymes that are resistant to the nonnucleoside inhibitors. We have investigated the enzymatic properties of two mutants of HIV-1 RT in which residues 181 and 188 were replaced by the corresponding amino acids in HIV-2 RT (tyrosine 181-->isoleucine and tyrosine 188-->leucine). The two tyrosine mutants closely resemble the wild-type HIV-1 RT in almost all the catalytic functions tested, including the heat stability, sensitivity of the DNA polymerase activity to inhibition by deoxynucleoside analogs, inhibition by the zinc chelator o-phenanthroline, and the Km values calculated for the DNA polymerase activity. There is, however, a slight difference in the effect of orthophenanthroline on the RNase H activity. In addition, there is a subtle disparity in the fidelity of DNA synthesis (analyzed by a mispair extension assay), thus indicating that these mutant RTs are not likely to confer any selective advantages or disadvantages to the variant virions over wild-type virus.
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PMID:Enzymatic properties of two mutants of reverse transcriptase of human immunodeficiency virus type 1 (tyrosine 181-->isoleucine and tyrosine 188-->leucine), resistant to nonnucleoside inhibitors. 752 32

Retroviral nucleocapsid (NC) proteins are highly basic, with one or two zinc fingers, and are required for virion formation, genomic RNA dimerization and packaging, and replication primer tRNA annealing to the viral RNA. We report here the first characterization of monoclonal antibodies directed against a retroviral nucleocapsid protein and their use to study the structure-function relationships of the nucleocapsid protein NCp7 of HIV-1. Four anti-NCp7 monoclonal antibodies (MAbs) have been generated by using NCp7 of HIV-1. The epitope targets of these MAbs were mapped using ELISA and BIAcore techniques. Whereas three of them are specific for epitopes located in the N and C termini of NCp7, the fourth one appears to be conformation specific. Interestingly, only two of these MAbs, the conformation-specific one and the MAb recognizing an N-terminal epitope are able to inhibit the RNA-binding and annealing activities of NCp7 as well as strong-stop DNA synthesis in vitro. The binding of the two other MAbs onto NCp7 either has no effect or enhances the NCp7-RNA interactions. These MAbs also display a differential recognition of the Gag polyprotein precursor, which makes them useful tools for studying NC protein maturation in the course of virion morphogenesis.
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PMID:Monoclonal antibody-mediated inhibition of RNA binding and annealing activities of HIV type 1 nucleocapsid protein. 752 35


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