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)

Feline immunodeficiency virus (FIV) causes a natural infection of domestic cats that resembles HIV-1 in pathogenesis and disease progression. Feline AIDS is characterized by depression of the CD4+ T cell population and fatal opportunistic infections. Maternal-fetal transmission of FIV readily occurs under experimental conditions, resulting in infected viable kittens and resorbed or arrested fetal tissues. Although both FIV and HIV use the chemokine receptor CXCR4 as a co-receptor, FIV does not utilize CD4 as the primary receptor. Rather, CD134 (OX40), a T cell activation antigen and co-stimulatory molecule, is the primary receptor for FIV. We hypothesized that placental expression of CD134 and CXCR4 may render the placenta vulnerable to FIV infection, possibly facilitating efficient vertical transmission of FIV, and impact pregnancy outcome. The purpose of this project was to quantify the relative expression of CD134 and CXCR4 mRNA from the term placentas of three groups of cats: uninfected queens producing viable offspring, experimentally-infected queens producing only viable offspring, and experimentally-infected queens producing viable offspring among mostly non-viable fetuses. Total RNA was extracted from term placental tissues from all groups of cats. Real-time one-step reverse transcriptase-PCR was used to measure gene expression. The FIV receptors CD134 and CXCR4 were expressed in all late term feline placental tissues. Placentas from FIV-infected queens producing litters of only viable offspring expressed more CD134 and CXCR4 mRNA than those from uninfected queens, suggesting that infection may cause upregulation of the receptors. On the other hand, placentas from FIV-infected cats with non-successful pregnancies expressed similar levels of CD134 mRNA and slightly less CXCR4 mRNA than those from uninfected queens. Thus, it appears that cells expressing these receptors may play a role in pregnancy maintenance.
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PMID:Expression of CD134 and CXCR4 mRNA in term placentas from FIV-infected and control cats. 1829 5

The folded 3D structures of peptides and proteins provide excellent starting points for the design of synthetic molecules that mimic key epitopes (or surface patches) involved in protein-protein and protein-nucleic acid interactions. Protein epitope mimetics (PEMs) may recapitulate not only the structural and conformational properties of the target epitope but also their biological activities. By transferring the epitope from a recombinant to a synthetic scaffold that can be produced by parallel combinatorial methods, it is possible to optimize properties through iterative cycles of library synthesis and screening, and even to evolve new biological activities. One very interesting scaffold is found in beta-hairpin motifs, which are used by many proteins to mediate molecular recognition events. This motif is readily amenable to PEM design, for example, by transplanting hairpin loop sequences from folded proteins onto hairpin-stabilizing templates, such as the dipeptide D-Pro-L-Pro. In addition, beta-hairpin peptidomimetics can also be exploited to mimic other types of epitopes, such as those based on alpha-helical secondary structures. The size and shape of beta-hairpin PEMs appear well suited for the design of inhibitors of both protein-protein and protein-nucleic acid interactions, endeavors that have so far proven difficult using small "drug-like" molecules. In recent work, it was shown that beta-hairpin PEMs can be designed that mimic the canonical conformations of antibody hypervariable loops, suggesting that novel small-molecule antibody mimics may be feasible. Using naturally occurring peptides as starting points, beta-hairpin mimetics have been discovered that possess antimicrobial activity, while others are potent inhibitors of the chemokine receptor CXCR4. Beta-hairpin PEMs have also been designed and optimized that mimic an alpha-helical epitope in p53 and so block its interaction with HDM2. A crystal structure of one HDM2-mimetic complex revealed how the surface of the protein had adapted to the shape of the hairpin, thereby enhancing inhibitor affinity. Small folded RNA motifs also make interesting targets for inhibitor design. For example, beta-hairpin mimetics have been designed and optimized that bind with high affinity and good selectivity to the TAR and RRE RNA motifs from HIV-1. Solution structures of the mimetics both free and bound to the RNA target provided some surprises, as well as an improved understanding of the mechanisms of binding. These mimetics represent still a relatively new family of RNA-binding molecules, but clearly one with potential for development into novel antiviral agents.
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PMID:Beta-hairpin peptidomimetics: design, structures and biological activities. 1841 73

The chemokine stromal cell-derived factor-1alpha (SDF-1alpha) binds to the chemokine receptor CXCR4 that couples to pertussis toxin-sensitive G-proteins of the G(i)/G(o)-family. CXCR4 plays a role in the pathogenesis of autoimmune diseases, human immunodeficiency virus infection and various tumors, fetal development as well as endothelial progenitor and T-cell recruitment. To this end, most CXCR4 studies have focused on the cellular level. The aim of this study was to establish a reconstitution system for the human CXCR4 that allows for the analysis of receptor/G-protein coupling at the membrane level. We wished to study specifically constitutive CXCR4 activity and the G-protein-specificity of CXCR4. We co-expressed N- and C-terminally epitope-tagged human CXCR4 with various G(i)/G(o)-proteins and regulator of G-protein signaling (RGS)-proteins in Sf9 insect cells. Expression of CXCR4, G-proteins, and RGS-proteins was verified by immunoblotting. CXCR4 coupled more effectively to Galpha(i1) and Galpha(i2) than to Galpha(i3) and Galpha(o) and insect cell G-proteins as assessed by SDF-1alpha-stimulated high-affinity steady-state GTP hydrolysis. The RGS-proteins RGS4 and GAIP enhanced SDF-1alpha-stimulated GTP hydrolysis. SDF-1alpha stimulated [(35)S]guanosine 5'-[gamma-thio]triphosphate (GTPgammaS) binding to Galpha(i2). RGS4 did not enhance GTPgammaS binding. Na(+) salts of halides did not reduce basal GTPase activity. The bicyclam, 1-[[1,4,8,11-tetrazacyclotetradec-1-ylmethyl)phenyl]methyl]-1,4,8,11-tetrazacyclotetradecane (AMD3100), acted as CXCR4 antagonist but was devoid of inverse agonistic activity. Halides reduced the maximum SDF-1alpha-stimulated GTP hydrolysis in the order of efficacy I(-) > Br(-) > Cl(-). In addition, salts reduced the potency of SDF-1alpha at activating GTP hydrolysis. From our data, we conclude the following: (1) Sf9 cells are a suitable system for expression of functionally intact human CXCR4; (2) Human CXCR4 couples effectively to Galpha(i1) and Galpha(i2); (3) There is no evidence for constitutive activity of CXCR4; (4) RGS-proteins enhance agonist-stimulated GTP hydrolysis, showing that GTP hydrolysis becomes rate-limiting in the presence of SDF-1alpha; (5) By analogy to previous observations made for the beta(2)-adrenoceptor coupled to G(s), the inhibitory effects of halides on agonist-stimulated GTP hydrolysis may be due to increased GDP-affinity of G(i)-proteins, reducing the efficacy of CXCR4 at stimulating nucleotide exchange.
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PMID:Functional reconstitution of the human chemokine receptor CXCR4 with G(i)/G (o)-proteins in Sf9 insect cells. 1852 57

Feline immunodeficiency virus (FIV) shares with T-cell tropic strains of human immunodeficiency virus type 1 (HIV-1) the use of the chemokine receptor CXCR4 for cellular entry. In order to map the interaction of the FIV envelope surface unit (SU) with CXCR4, full-length FIV SU-Fc as well as constructs with deletions of extended loop L2, V3, V4, or V5 were produced in stable CHO cell lines. Binding studies were performed using these proteins on 3201 cells (CXCR4(hi) CD134(-)), with or without the CXCR4 inhibitor AMD3100. The findings established that SU binding to CXCR4 specifically requires the V3 region of SU. Synthetic peptides spanning the V3 region as well as a panel of monoclonal antibodies (MAbs) to SU were used to further map the site of CXCR4 interaction. Both the SU V3-specific antibodies and the full-length V3 peptide potently blocked binding of SU to CXCR4 and virus entry. By using a set of nested peptides overlapping a region of SU specifically recognized by CD134-dependent neutralizing V3 MAbs, we showed that the neutralizing epitope and the region required for CXCR4 binding are within the same contiguous nine-amino-acid sequence of V3. Site-directed mutagenesis was used to reveal that serine 393 and tryptophan 394 at the predicted tip of V3 are required to facilitate entry into the target cell via CXCR4. Although the amino acid sequences are not identical between FIV and HIV, the ability of FIV to bind and utilize both feline and human CXCR4 makes the feline model an attractive venue for development of broad-based entry antagonists.
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PMID:Mapping of the CXCR4 binding site within variable region 3 of the feline immunodeficiency virus surface glycoprotein. 1859 86

The chemokine receptor CXCR4 and its ligand, stromal cell-derived factor-1 (SDF-1), play important roles in hematopoiesis regulation, lymphocyte activation, and trafficking, as well as in developmental processes, including organogenesis, vascularization, and embryogenesis. The receptor is also involved in HIV infection and tumor growth and metastasis. Antagonists of CXCR4 have been widely evaluated for drugs against HIV and tumors. In an effort to identify novel CXCR4 antagonists, we screened a small library of compounds derived from marine organisms and found bryostatin-5, which potently inhibits chemotaxis induced by SDF-1 in Jurkat cells. Bryostatin-5 is a member of the macrolactones, and its analogue bryostatin-1 is currently being evaluated in clinical trials for its chemotherapeutic potential. The involvement of bryostatins in the SDF-1/CXCR4 signaling process has never been reported. In this study, we found that bryostatin-5 potently inhibits SDF-1-induced chemotaxis but does not affect serum-induced chemotaxis. Further studies indicate that this inhibitory effect is not due to receptor antagonism but rather to bryostatin-5-induced receptor desensitization and down-regulation of cell surface CXCR4. We also show that these effects are mediated by the activation of conventional protein kinase C.
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PMID:Bryostatin-5 blocks stromal cell-derived factor-1 induced chemotaxis via desensitization and down-regulation of cell surface CXCR4 receptors. 1897 9

The interaction of the chemokine receptor CXCR4 with its ligand CXCL12 is involved in many biological processes such as hematopoesis, migration of immune cells, as well as in cancer metastasis. CXCR4 also mediates the infection of T-cells with X4-tropic HIV functioning as a coreceptor for the viral envelope protein gp120. Here, we describe highly potent, selective CXCR4 inhibitors that block CXCR4/CXCL12 interactions in vitro and in vivo as well as the infection of target cells by X4-tropic HIV.
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PMID:Orally bioavailable isothioureas block function of the chemokine receptor CXCR4 in vitro and in vivo. 1905 68

Seven transmembrane (7TM) G-protein-coupled receptor (GPCR) families are important targets for drug discovery, and specific antagonists for GPCR can accelerate research in the field of medicinal chemistry. The chemokine receptor CXCR4 is a GPCR that possesses a unique ligand CXCL12/stromal cell-derived factor-1 (SDF-1). The interaction between CXCL12 and CXCR4 is essential for the migration of progenitor cells during embryonic development of the cardiovascular, hemopoietic and central nervous systems, and also involved in several intractable disease processes, including HIV infection, cancer cell metastasis, progression of acute and chronic leukemias, rheumatoid arthritis and pulmonary fibrosis. Thus, CXCR4 may be an important therapeutic target in all of these diseases, and various CXCR4 antagonists have been proposed as potential drugs. Fourteen-mer peptides, T140 and its analogs, and downsized cyclic pentapeptides have been developed by us as potent CXCR4 antagonists. This article describes the development of a number of specific CXCR4 antagonists in our laboratory, including downsizing.
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PMID:Exploratory studies on development of the chemokine receptor CXCR4 antagonists toward downsizing. 1978 93

Allelic differences of chemokine (C-C motif ) receptor 5 (CCR5) and CCR2, as well as the ligand for the chemokine receptor CXCR4, stromal-derived factor (SDF-1), are known to suppress HIV-1 transmission and to be involved in delay in HIV-1 disease progression. The aim of our study was to investigate the frequencies of four mutations that confer resistance to HIV-1: CCR5-Delta32, CCR5-m303, CCR2-64I, and SDF1-3'A among Bahrainis. We have studied the DNA polymorphisms in 304 unrelated healthy Bahraini individuals without any known history of HIV-1 infection or AIDS symptoms. The CCR5-Delta32 mutation was detected by PCR analysis, while the CCR5-m303, CCR2-64I, and SDF1-3'A mutations were detected by PCR-restriction fragment length polymorphism (PCR-RFLP) tests. Allele frequencies and the fit to the Hardy-Weinberg equilibrium were evaluated using the Arlequin population genetics application. The frequencies of the CCR5-Delta32, CCR2-64I, and SDF1-3'A alleles were 2.8%, 8.9%, and 26.5%, respectively. No mutant alleles were detected for the CCR5-m303 mutation in 304 individuals. We estimated the risk of AIDS onset (relative hazard), computed from the three-locus genotype data. This is the first report of these four mutations conferring resistance to HIV-1 in the Bahraini population. The presence of the CCR5-Delta32 allele among Bahrainis may be attributed to the admixture with people of European descent. The CCR2-64I allele and especially the SDF1-3'A allele are predominant in the Bahraini population and may be associated with resistance to fast HIV-1 infection in Bahrainis, and thus their genotyping can be used for prognosis in HIV-infected individuals.
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PMID:Distribution of four HIV type 1-resistance polymorphisms (CCR5-Delta32, CCR5-m303, CCR2-64I, and SDF1-3'A) in the Bahraini population. 1980 15

Bis-tetraazamacrocycles such as the bicyclam AMD3100 (1) are a class of potent and selective anti-HIV-1 agents that inhibit virus replication by binding to the chemokine receptor CXCR4, the coreceptor for entry of X4 viruses. By sequential replacement and/or deletion of the amino groups within the azamacrocyclic ring systems, we have determined the minimum structural features required for potent antiviral activity in this class of compounds. All eight amino groups are not required for activity, the critical amino groups on a per ring basis are nonidentical, and the overall charge at physiological pH can be reduced without compromising potency. This approach led to the identification of several single ring azamacrocyclic analogues such as AMD3465 (3d), 36, and 40, which exhibit EC(50)'s against the cytopathic effects of HIV-1 of 9.0, 1.0, and 4.0 nM, respectively, antiviral potencies that are comparable to 1 (EC(50) against HIV-1 of 4.0 nM). More importantly, however, the key structural elements of 1 required for antiviral activity may facilitate the design of nonmacrocyclic CXCR4 antagonists suitable for HIV treatment via oral administration.
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PMID:Synthesis and structure-activity relationships of azamacrocyclic C-X-C chemokine receptor 4 antagonists: analogues containing a single azamacrocyclic ring are potent inhibitors of T-cell tropic (X4) HIV-1 replication. 2004 38

The chemokine receptor CXCR4 is shared by primary and laboratory-adapted strains of feline immunodeficiency virus (FIV) for viral entry. Our previous studies implicated a contiguous nine-amino-acid region of the V3 loop of the FIV envelope surface as important in CXCR4 binding and virus entry. The binding is specific for CXCR4 since it can be inhibited by AMD3100, a selective CXCR4 inhibitor. Additional site-directed mutagenesis was used to further reveal the key residues. Binding studies indicated that basic residues R395, K397, R399 as well as N398 are critical for CXCR4 binding. The effect of other amino acid residues on receptor binding depends on the type of amino acid residue substituted. The binding study results were confirmed on human CXCR4-expressing SupT1 cells and correlated with entry efficiency using a virus entry assay. Amino acid residues critical for CXCR4 are not critical for interactions with the primary binding receptor CD134, which has an equivalent role as CD4 for HIV-1 binding. The ELISA results show that W394 and W400 are crucial for the recognition by neutralizing anti-V3 antibodies. Since certain strains of HIV-1 also use CXCR4 as the entry receptor, the findings make the feline model attractive for development of broad-based entry antagonists and for study of the molecular mechanism of receptor/virus interactions.
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PMID:Fine definition of the CXCR4-binding region on the V3 loop of feline immunodeficiency virus surface glycoprotein. 2050 26


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