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)

Human immunodeficiency virus type 1 integrase (HIV-1 IN) catalyzes both 3'-donor processing and strand transfer reactions. Previous studies have determined that the N-terminal region, a putative zinc finger, is capable of binding Zn2+. The function of zinc coordination to this domain, however, is still unknown. In this report, we present evidence that Mg2+-dependent 3'-donor processing by HIV-1 IN is enhanced by the addition of Zn2+ in vitro. This activity is inhibited in the presence of the chelator 1,10-phenanthroline (OP). In addition, the Mg2+-dependent 3'-donor processing activity is more sensitive to the concentration of IN than is the Mn2+-dependent activity. A combination of dimethyl sulfoxide (DMSO) and poly(ethylene glycol) (PEG) was found to further activate the Mg2+-dependent 3'-donor processing activity while diminishing the Mn2+-dependent activity. These results suggest factors such as substrate-length, concentration of IN, Zn2+ coordination, and protein-protein interactions are important for efficient and specific donor processing activity with Mg2+ in vitro.
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PMID:Zinc stimulates Mg2+-dependent 3'-processing activity of human immunodeficiency virus type 1 integrase in vitro. 862 7

To date, the effective management of HIV-1 infection by anti-retroviral drugs has proved remarkably difficult to achieve. This is primarily due to the ease with which HIV-1 becomes resistant to drugs which initially may be very effective at blocking viral replication. In a recent issue of Science, two promising new AIDS treatments were reported. The first described the use of retroviral-type zinc finger structures found in the HIV-1 nucleocapsid protein as targets for antiretroviral drugs. THe second demonstrated the feasibility of the reverse transcriptase inhibitor (R)-9-(2-phosphonylmethoxypropyl) adenine as a postexposure prophylaxis in blocking HIV-1 infection.
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PMID:New strategies for treating AIDS. 863 56

To clarify the physiological function of two zinc finger motifs in the nucleocapsid (NC) domain of the Gag protein of human immunodeficiency virus type 1 (HIV-1), we changed cysteine to serine in either of the two motifs or both by site-directed mutagenesis. Viral infectivity was lost by any of the mutations, but their effects appeared differently in the respective mutants. Northern blot analysis showed that the first finger mutant was far less efficient (approximately 10% of the wild type) in genomic RNA encapsidation and that the dual mutant of both fingers completely failed to encapsidate the RNA. In contrast, the second finger mutant retained its ability for RNA encapsidation with an efficiency similar to that of the wild type. Immunoblot analysis of the lysates of CD4-positive M8166 cells transfected with the mutant proviral DNAs showed that the processing of Gag precursors was delayed in two mutant viruses having alterations in the first finger sequence, whereas the processing of the second finger mutant appeared to be normal. On the other hand, immunoblot analysis of the virus particles showed that the second finger mutant particles contained some proteins that were thought to be degradation products of p24CA. Electron microscopic observation showed that all particles of these mutant viruses were morphologically alike except that they had a slightly larger diameter than that of the wild type. These results indicate that these finger motifs of HIV-1 NC protein do not function equivalently. Namely, the first finger is primarily responsible for RNA encapsidation and the second is required for stabilization of virus particles.
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PMID:Mutational analysis of two zinc finger motifs in HIV type 1 nucleocapsid proteins: effects on proteolytic processing of Gag precursors and particle formation. 873 31

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

After a retrovirus particle is released from the cell, the dimeric genomic RNA undergoes a change in conformation. We have previously proposed that this change, termed maturation of the dimer, is due to the action of nucleocapsid (NC) protein on the RNA within the virus particle. We now report that treatment of a 345-base synthetic fragment of Harvey sarcoma virus RNA with recombinant or synthetic HIV-1 NC protein converts a less stable form of dimeric RNA to a more stable form. This phenomenon thus appears to reproduce the maturation of dimeric retroviral RNA in a completely defined system in vitro. To our knowledge, maturation of dimeric RNA within a retrovirus particle is the first example of action of an "RNA chaperone" protein in vivo. Studies with mutant NC proteins suggest that the activity depends upon basic amino acid residues flanking the N-terminal zinc finger and upon residues within the N-terminal finger, including an aromatic amino acid, but do not require the zinc finger structures themselves.
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PMID:HIV-1 nucleocapsid protein induces "maturation" of dimeric retroviral RNA in vitro. 875 17

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

Silencing is an epigenetic form of transcriptional regulation whereby genes are heritably, but not necessarily permanently, inactivated. We have identified the Saccharomyces cerevisiae genes SAS2 and SAS3 through a screen for enhancers of sir1 epigenetic silencing defects. SAS2, SAS3 and a Schizosaccharomyces pombe homologue are closely related to several human genes, including one associated with acute myeloid leukaemia arising from the recurrent translocation t(8;16)(p11;p13) and one implicated in HIV-1 Tat interactions. All of these genes encode proteins with an atypical zinc finger and well-conserved similarities to acetyltransferases. Sequence similarities and yeast mutant phenotypes suggest that SAS-like genes function in transcriptional regulation and cell-cycle exit and reveal novel connections between transcriptional silencing and human disease.
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PMID:Yeast SAS silencing genes and human genes associated with AML and HIV-1 Tat interactions are homologous with acetyltransferases. 914 Apr 6

In an earlier study on minus-strand DNA synthesis catalyzed by murine leukemia virus reverse transcriptase, we described a prominent pause site near the polypurine tract (J. Guo, W. Wu, Z. Y. Yuan, K. Post, R. J. Crouch, and J. G . Levin, Biochemistry 34:5018-5029, 1995). We now report that pausing at this site is due to a stem-loop structure in the RNA template, formed by interaction of a number of bases in the polypurine tract, including the six G's, and a 3' sequence which includes four C's. Addition of human immunodeficiency virus type 1 (HIV-1) nucleocapsid (NC) protein to reverse transcriptase reactions reduces pausing by approximately 8- to 10-fold and stimulates synthesis of full-length DNA. Thus, NC functions as an accessory protein during elongation of minus-strand DNA and increases the efficiency of DNA synthesis, in this case, by apparently destabilizing a region of secondary structure in the template. Since NC is associated with genomic RNA in the viral core and is likely to be part of a viral replication complex, these results suggest that NC may also promote efficient DNA synthesis during virus replication. Mutational analysis indicates that the features of HIV-1 NC which are important for reduction of pausing include the basic amino acids flanking the first zinc finger, the zinc fingers, and the cysteine and aromatic amino acids within the fingers. These findings suggest that reverse transcription might be targeted by drugs which inactivate the zinc fingers of HIV-1 NC.
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PMID:Human immunodeficiency virus type 1 nucleocapsid protein reduces reverse transcriptase pausing at a secondary structure near the murine leukemia virus polypurine tract. 879 60

Conservation of the Cys-Xaa2-Cys-Xaa4-His-Xaa4-Cys retroviral zinc finger sequences and their absolute requirement in both the early and late phases of retroviral replication make these chemically reactive structures prime antiviral targets. We recently reported that select 2,2'-dithiobisbenzamides (DIBAs) chemically modify the zinc finger Cys residues, resulting in release of zinc from the fingers and inhibition of HIV replication. In the current study we surveyed 21 categories of disulfide-based compounds from the chemical repository of the National Cancer Institute for their capacity to act as retroviral zinc finger inhibitors. Aromatic disulfides that exerted anti-HIV activity tended to cluster in the substituted aminobenzene, benzoate, and benzenesulfonamide disulfide subclasses. Only one thiuram derivative exerted moderate anti-HIV activity, while a number of nonaromatic thiosulfones and miscellaneous disulfide congeners were moderately antiviral. Two compounds (NSC 20625 and NSC 4493) demonstrated anti-cultures. The two compounds chemically modified the p7NC zinc fingers in two separate in vitro assays, and interatomic surface molecular modeling docked the compounds efficiently but differentially into the zinc finger domains. The combined efforts of rational drug selection, cell-based screening, and molecular target-based screening led to the identification of zinc finger inhibitors that can now be optimized by medicinal chemistry for the development of biopharmaceutically useful anti-HIV agents.
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PMID:Evaluation of selected chemotypes in coupled cellular and molecular target-based screens identifies novel HIV-1 zinc finger inhibitors. 880 51

The nucleocapsid (NC) protein of human immunodeficiency virus type-1 (HIV-1) contains two zinc finger motifs (ZFMs), and binds specifically to the packaging signal which is located in the 5' leader sequence of the viral genomic RNA between the first splice donor and the gag initiator codon (AUG). In this study, we analyzed the specificity of the binding of the corresponding region of HIV-2 (Region 3) to its NC protein (NCp8), by performing a competitive ultraviolet (UV) cross-linking assay using in vitro-synthesized 32P-labeled and unlabeled RNAs corresponding to a sequence between the primer binding site and the gag AUG (Region 1). Binding of 32P-labeled Region 1 RNA to NCp8 was inhibited specifically by adding unlabeled Region 1 and 3 RNAs and no specific binding was detected using deletion mutant peptides of NCp8. These findings suggest that the region(s) which bind(s) specifically to HIV-2 NCp8 lie(s) between the first splice donor and the gag AUG in the 5' leader sequence and that NCp8 is the minimum binding region responsible for the specific binding of the region downstream of the first splice donor site of HIV-2 RNA.
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PMID:Binding properties of human immunodeficiency virus type-2 (HIV-2) RNA corresponding to the packaging signal to its nucleocapsid protein. 888 67


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