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)

HIV cellular entry is a multistep process that requires the interaction of a viral envelope glycoprotein (gp120) and a host receptor (CD4) followed by binding to a co-receptor. The CC-chemokine receptor 5 (CCR5) and CXC-chemokine receptor 4 (CXCR4) have been identified as the major HIV co-receptors and therefore are promising targets for the development of new anti-HIV drugs. CXCR4 is also involved in several diseases such as angiogenesis, metabolic and neurological disorders, rheumatoid arthritis and in different forms of metastatic cancer. Herein, we present a review focusing on small molecule CXCR4 antagonists. These compounds are divided into 11 classes that include cyclic penta- and tetrapeptides, diketopiperazine mimetics, bicyclams, non-bicyclams, tetrahydroquinolines, thiazolylisothiourea derivatives, benzodiazepines, alkyl amine analogs and non-peptides derivatives, dipicolylamine-zinc(II) complexes, ampelopsin and distamycin analogs. The most advanced CXCR4 antagonists documented are bicyclam derivatives, which are specific CXCR4 antagonists and exhibit potency in the nanomolar range. Further development of selective CXCR4 antagonists continues to be crucial for the design of second generation of anti-HIV drugs. We aim to provide a comprehensive summary of diverse structural templates that could be useful for optimization and discovery of novel CXCR4 antagonists.
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PMID:Small molecules anti-HIV therapeutics targeting CXCR4. 1828 65

The CC-chemokine receptor 5 (CCR5), a membrane protein belonging to the G-protein coupled receptor super-family, has been identified as an essential co-receptor for HIV entry into the cells, and small molecules that inhibit HIV entry by targeting CCR5 have been in fast development as antiviral agents. This review focuses on computational studies of predicting the CCR5 structure and its interactions with known small molecule inhibitors and discusses how the recently solved GPCR structures would provide new insights into the modeling of CCR5-inhibitor binding. In addition, this review pays a particular attention to the design of the inhibitors that specifically interrupt the viral entry co-receptor activity of CCR5 while preserving its normal chemokine receptor function to minimize side effects and toxicity.
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PMID:HIV co-receptor CCR5: structure and interactions with inhibitors. 1951 82

It has been described that polymorphonuclear neutrophils (PMNs) enhance the replication of CC-chemokine receptor 5/macrophage-tropic (R5) HIV in cultures of monocyte-derived macrophages (MDMs). In this study, the inhibitory effect of glycyrrhizin (GL) on R5 HIV replication influenced by PMNs was investigated in MDM cultures. The replication of R5 HIV in MDMs was greatly enhanced when cells were co-cultured with freshly isolated PMNs (syngeneic to MDMs). When GL was added to this culture, however, the viral replication enhanced by PMNs was completely inhibited. CCL2 and interleukin 10 (IL-10) were produced in cultures of PMNs exposed to R5 HIV, and the replication of R5 HIV was greatly enhanced in MDM cultures supplemented with a mixture of recombinant CCL2 and IL-10. However, CCL2 and IL-10 were not produced by PMNs exposed to R5 HIV, when GL was added to the cultures. In the presence of GL, these soluble factors were not detected in co-cultures of MDMs and PMNs exposed to R5 HIV. In addition, the replication of R5 HIV in MDMs stimulated with CCL2 and IL-10 was not directly influenced by GL. These results indicated that GL suppresses the PMN-dependent increase of R5 HIV replication in MDMs through inhibiting CCL2/IL-10 production by PMNs stimulated with R5 HIV.
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PMID:Inhibitory effect of glycyrrhizin on the neutrophil-dependent increase of R5 HIV replication in cultures of macrophages. 1952

The gastrointestinal mucosa is a target of many sexually transmitted infections, and major advances have increased our understanding of the consequences of such infections within the gastrointestinal system. HIV-1 is associated with a marked loss of mucosal CD4(+) T cells that express CC-chemokine receptor 5. This process seems to be more rapid and more severe in mucosa-associated lymphoid tissue than in the peripheral blood. Mechanistic insights into the underlying cause of acute and chronic gastrointestinal damage with HIV infection-microbial translocation, defects in intestinal epithelial barrier function and activation of a systemic immune response-have also been achieved. Increased understanding of the pathogenesis of mucosal HIV-1 infection may identify therapeutic targets to restore immunological function and the integrity of the intestinal mucosal epithelial barrier. The increasing prevalence of lymphogranuloma venereum in Europe, mostly in HIV-positive men who have sex with men, suggests a change in the epidemiology of what was previously considered to be a 'tropical' disease. The increasing incidence of acute HCV infection transmitted via sexual contact has also been fueled by high-risk sexual behaviors among men who have sex with men, many of whom are also HIV-positive. The first part of this Review discusses the pathogenesis and gastrointestinal complications of HIV infection, and the second part summarizes advances in our understanding of other sexually transmitted infections of the gastrointestinal system.
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PMID:Advances in sexually transmitted infections of the gastrointestinal tract. 1970 79

Platelet factor 4 (CXCL4), a member of the CXC chemokine subfamily released in high amounts by activated platelets, has been identified as a monocyte survival factor that induces monocyte differentiation into macrophages. Although CXCL4 has been shown to have biological effects unique to chemokines, nothing is known about the role of CXCL4-derived human macrophages or CXCL4 in human immunodeficiency virus (HIV) disease. In this study, CXCL4-derived macrophages are compared with macrophage-colony stimulating factor (M-CSF)-derived macrophages for their ability to support HIV-1 replication. We show that CXCL4-derived macrophages can be infected with macrophage-tropic HIV-1 that uses either CC-chemokine receptor 5 (CCR5) or CXC-chemokine receptor 4 (CXCR4) as a co-receptor for viral entry. We also find that M-CSF and the chemokines, monocyte chemoattractant protein 1 (MCP-1; CCL2) and macrophage-inflammatory-protein-1-alpha (MIP-1alpha; CCL3) are produced upon R5- and X4-tropic HIV-1 replication in both M-CSF- and CXCL4-derived human macrophages. In addition, CXCL4 added to M-CSF-derived macrophages after virus adsorption and maintained throughout the infection enhances HIV-1 replication. We thus propose a novel role for CXCL4 in HIV disease.
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PMID:Platelet factor 4 (CXCL4) facilitates human macrophage infection with HIV-1 and potentiates virus replication. 1977 94

CC-chemokine receptor 5 (CCR5) belongs to the G protein-coupled receptor (GPCR) family and plays important roles in the inflammatory response. In addition, its ligands inhibit the HIV infection. Structural analyses of CCR5 have been hampered by its instability in the detergent-solubilized form. Here, CCR5 was reconstituted into high density lipoprotein (rHDL), which enabled CCR5 to maintain its functions for >24 h and to be suitable for structural analyses. By applying the methyl-directed transferred cross-saturation (TCS) method to the complex between rHDL-reconstituted CCR5 and its ligand MIP-1alpha, we demonstrated that valine 59 and valine 63 of MIP-1alpha are in close proximity to CCR5 in the complex. Furthermore, these results suggest that the protective influence on HIV-1 infection of a SNP of MIP-1alpha is due to its change of affinity for CCR5. This method will be useful for investigating the various and complex signaling mediated by GPCR, and will also provide structural information about the interactions of other GPCRs with lipids, ligands, G-proteins, and effector molecules.
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PMID:NMR analyses of the interaction between CCR5 and its ligand using functional reconstitution of CCR5 in lipid bilayers. 2042 99

The inherent instability of heptahelical G protein-coupled receptors (GPCRs) during purification and reconstitution is a primary impediment to biophysical studies and to obtaining high-resolution crystal structures. New approaches to stabilizing receptors during purification and screening reconstitution procedures are needed. Here we report the development of a novel homogeneous time-resolved fluorescence assay (HTRF) to quantify properly folded CC-chemokine receptor 5 (CCR5). The assay permits high-throughput thermal stability measurements of femtomole quantities of CCR5 in detergent and in engineered nanoscale apolipoprotein-bound bilayer (NABB) particles. We show that recombinantly expressed CCR5 can be incorporated into NABB particles in high yield, resulting in greater thermal stability compared with that of CCR5 in a detergent solution. We also demonstrate that binding of CCR5 to the HIV-1 cellular entry inhibitors maraviroc, AD101, CMPD 167, and vicriviroc dramatically increases receptor stability. The HTRF assay technology reported here is applicable to other membrane proteins and could greatly facilitate structural studies of GPCRs.
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PMID:Direct measurement of thermal stability of expressed CCR5 and stabilization by small molecule ligands. 2115 86

CC-chemokine receptor 5 (CCR5) is a specific co-receptor allowing the entry of human immunodeficiency virus type 1 (HIV-1). The LC4 region in CCR5 is required for HIV-1 entry into the cells. In this study, the solution structure of LC4 in SDS micelles was elucidated by using standard 1H two-dimensional NMR spectroscopy, circular dichroism, and fluorescence quenching. The LC4 structure adopts two helical structures, whereas the C-terminal part remains unstructured. The positions in which LC4 binds to the HIV-1 inhibitory peptide LC5 were determined by docking calculations in addition to NMR data. The poses showed the importance of the hydrophobic interface of the assembled structures. The solution structure of LC4 elucidated in the present work provides a structural basis for further studies on the HIV-1 inhibitory function of the LC4 region.
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PMID:Solution structure of LC4 transmembrane segment of CCR5. 2164 80

External guide sequences (EGSs) represent a new class of RNA-based gene-targeting agents, consist of a sequence complementary to a target mRNA, and render the target RNA susceptible to degradation by ribonuclease P (RNase P). In this study, EGSs were constructed to target the mRNA encoding human CC-chemokine receptor 5 (CCR5), one of the primary coreceptors for HIV. An EGS RNA, C1, efficiently directed human RNase P to cleave the CCR5 mRNA sequence in vitro. A reduction of about 70% in the expression level of both CCR5 mRNA and protein and an inhibition of more than 50-fold in HIV (R5 strain Ba-L) p24 production were observed in cells that expressed C1. In comparison, a reduction of about 10% in the expression of CCR5 and viral growth was found in cells that either did not express the EGS or produced a "disabled" EGS which carried nucleotide mutations that precluded RNase P recognition. Furthermore, the same C1-expressing cells that were protected from R5 strain Ba-L retained susceptibility to X4 strain IIIB, which uses CXCR4 as the coreceptor instead of CCR5, suggesting that the RNase P-mediated cleavage induced by the EGS is specific for the target CCR5 but not the closely related CXCR4. Our results provide direct evidence that EGS RNAs against CCR5 are effective and specific in blocking HIV infection and growth. These results also demonstrate the feasibility to develop highly effective EGSs for anti-HIV therapy.
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PMID:RNase P-associated external guide sequence effectively reduces the expression of human CC-chemokine receptor 5 and inhibits the infection of human immunodeficiency virus 1. 2350 33

HIV-1 infection requires the presence of the CD4 receptor on the target cell surface and a coreceptor, predominantly CC-chemokine receptor 5 (CCR5). It has been shown that individuals who are homozygous for a defective CCR5 gene are protected from HIV-1 infection. A novel self-inactivating lentiviral vector LVsh5/C46 (Cal-1) has been engineered to block HIV-1 infection with two viral entry inhibitors, conferring resistance to HIV-1 infection from both CCR5 and CXCR4 tropic strains. Cal-1 encodes a short hairpin RNA (sh5) to downregulate CCR5 and C46, an HIV-1 fusion inhibitor. Gene therapy by Cal-1 is aimed at transducing CD4+ T cells and CD34+ hematopoietic stem/progenitor cells in an autologous transplant setting. Pre-clinical safety and efficacy studies in vitro and in vivo (humanized mouse model and nonhuman primates) have shown that Cal-1 is safe with no indication of any toxicity risk and acts to decrease viral load and increase CD4 counts. Two clinical trials are underway using Cal-1: a phase I/II study to assess safety and feasibility in an adult HIV-1-positive population not on antiretroviral therapy (ART); and a second Fred Hutchinson Investigator Initiated phase I study to assess safety and feasibility in adults with HIV-1-associated non-Hodgkin or Hodgkin lymphoma.
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PMID:Cell-Delivered Entry Inhibitors for HIV-1: CCR5 Downregulation and Blocking Virus/Membrane Fusion in Defending the Host Cell Population. 2790 41


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