UMLS:C0019693 - FACTA Search

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Query: UMLS:C0019693 (HIV)
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Human CD34(+) hematopoietic progenitor cells obtained from bone marrow (BM), umbilical cord blood (UCB), and mobilized peripheral blood (MPB) were purified and investigated for the expression of the chemokine receptor CXCR4 and its ligand, stromal cell-derived factor-1 (SDF-1). CXCR4 was found present on the cell surface of all CD34(+) cells, although it was expressed at lower density on MPB with respect to BM CD34(+) cells. Freshly isolated and in vitro-cultured CD34(+) cells also coexpressed SDF-1 mRNA, as determined by reverse transcriptase-polymerase chain reaction (RT-PCR). Of interest, CD34(+)/CD38(+) committed progenitor cells, unlike primitive CD34(+)/CD38(-) cells, expressed SDF-1 mRNA. Supernatants from in vitro-cultured CD34(+) cells contained substantial (3 to 8 ng/mL) amounts of SDF-1 by enzyme-linked immunosorbent assay and induced migration of CD34(+) cells. Because CD34(+) cells express low levels of CD4, the primary receptor of the human immunodeficiency virus (HIV), and CXCR4 is a coreceptor for T-cell tropic (X4) HIV strains, we investigated the susceptibility of CD34(+) cells to infection by this subset of viruses. Lack of productive infection was almost invariably observed as determined by a conventional RT activity in culture supernatants and by real-time PCR for HIV DNA in CD34(+) cells exposed to both laboratory adapted (LAI) and primary (BON) X4 T-cell tropic HIV-1 strain. Soluble gp120 Env (sgp120) from X4 HIV-1 efficiently blocked binding of the anti-CD4 Leu3a monoclonal antibody (MoAb) to either human CD4(+) T cells or CD34(+) cells. In contrast, sgp120 interfered with an anti-CXCR4 MoAb binding to human T lymphocytes, but not to CD34(+) cells. However, CXCR4 on CD34(+) cells was downregulated by SDF-1. These results suggest that CXCR4 and its ligand SDF-1 expressed in CD34(+) progenitors may play an important role in regulating the local and systemic trafficking of these cells. Moreover, these findings suggest multiple and potentially synergistic mechanisms at the basis of the resistance of CD34(+) cells to X4 HIV infection, including their ability to produce SDF-1, and the lack of CXCR4 internalization following gp120 binding to CD4.
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PMID:Human CD34(+) cells express CXCR4 and its ligand stromal cell-derived factor-1. Implications for infection by T-cell tropic human immunodeficiency virus. 1038 99

Studies have demonstrated that the beta-chemokines RANTES, MIP-1alpha, and MIP-1beta suppress human immunodeficiency type 1 (HIV-1) replication in vitro. Infection with HIV-1 requires expression of CD4 antigen and the chemokine receptor CXCR4 (X4) or CCR5 (R5) on the surface of target cells. The engagement of these receptors with the viral surface proteins is essential for the membrane fusion process. This study investigated the anti-HIV-1 activity of a derivative of RANTES, the CCR5 antagonist aminooxypentane (AOP)-RANTES, on R5 HIV-1 isolates in peripheral blood mononuclear cells. In drug exposure experiments, AOP-RANTES efficiently inhibited viral replication of HIV-1 R5 strains, with a viral breakthrough observed after the withdrawal of the compound. The HIV-1-specific proliferative capacity was maintained under all conditions when compared with controls. An increase in IFN-gamma production accompanied by a parallel decrease in the generation of IL-10 was observed following the in vitro exposure of cells to AOP-RANTES in the presence of three of four HIV-1 R5 isolates. These experiments confirmed that the chemokine receptor antagonist AOP-RANTES was effective as an inhibitor of HIV-1 R5 strain infectivity in peripheral blood mononuclear cells. The capacity of this compound to maintain HIV-1-specific proliferative activity with a shift toward a type 1 cytokine profile makes this compound a unique molecule, one adopting an immunological pathway to limit HIV-1 infection.
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PMID:Aminooxypentane-RANTES, an inhibitor of R5 human immunodeficiency virus type 1, increases the interferon gamma to interleukin 10 ratio without impairing cellular proliferation. 1040 22

Bis-tetraazamacrocycles such as the bicyclam AMD3100 are a class of potent and selective anti-HIV-1 and HIV-2 agents that inhibit virus replication by binding to the chemokine receptor CXCR4, the co-receptor for entry of X4 viruses. With the aim of optimizing the anti-HIV-1 and HIV-2 activity of bis-azamacrocycles, a series of analogues were synthesized which contain neutral heteroatom (oxygen, sulfur) or heteroaromatic (of lower pK(a) than a secondary amine) replacements for the amino groups of AMD3100. The introduction of one or more heteroatoms such as oxygen or sulfur into the macrocyclic ring of p-phenylenebis(methylene)-linked dimers (to give N(3)X or N(2)X(2) bis-macrocycles) gave analogues with substantially reduced anti-HIV-1 (III(B)) and anti-HIV-2 (ROD) potency. In addition, the bis-sulfur analogue was also markedly more cytotoxic to MT-4 cells. However, bis-tetraazamacrocycles featuring a single pyridine group incorporated within the macrocyclic framework exhibited anti-HIV-1 and HIV-2 potency comparable to that of their saturated, aliphatic counterparts. The p-phenylenebis(methylene)-linked dimer of the py[14]aneN(4) macrocycle inhibited HIV-1 replication at a 50% effective concentration (EC(50)) of 0.5 microM while remaining nontoxic to MT-4 cells at concentrations approaching 200 microM. A series of analogues containing macrocyclic heteroaromatic groups of varying pK(a) were also synthesized, and their ability to inhibit HIV replication was evaluated. Replacing the pyridine moiety of the py[14]aneN(4) macrocyclic ring with pyrazine or pyridine groups substituted in the 4-position (with electron-withdrawing or -donating groups) either reduced antiviral potency or increased cytotoxicity to MT-4 cells. Finally, we synthesized a series of analogues in which the ring size of the bis-pyridyl macrocycles was varied between 12 and 16 members per ring including the py[iso-14]aneN(4) ring system, an isomer of the py[14]aneN(4) macrocycle. The p-phenylenebis(methylene)-linked dimer of the py[iso-14]aneN(4) (AMD3329) displayed the highest antiviral activity of the bis-azamacrocyclic analogues reported to date, exhibiting EC(50)'s against the cytopathic effects of HIV-1 and HIV-2 replication of 0.8 and 1.6 nM, respectively, that is, about 3-5-fold lower than the EC(50) of AMD3100. AMD3329 also inhibited the binding of a specific CXCR4 mAb and the Ca(2+) flux induced by SDF-1alpha, the natural ligand for CXCR4, more potently than AMD3100. Furthermore, AMD3329 also interfered with virus-induced syncytium formation at an EC(50) of 12 nM.
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PMID:Synthesis and structure-activity relationships of phenylenebis(methylene)-linked bis-azamacrocycles that inhibit HIV-1 and HIV-2 replication by antagonism of the chemokine receptor CXCR4. 1050 45

Negatively charged albumins (NCAs) have been identified as potent inhibitors of HIV-1 replication in vitro. Time of addition studies suggest that succinylated and aconitylated human serum albumin (Suc-HSA and Aco-HSA) act at an early stage of the virus life cycle, and surface plasmon resonance (BIAcore) experiments have confirmed a direct interaction of NCAs with HIV-1 gp120. Resistance to Suc-HSA and Aco-HSA was analyzed by characterizing HIV-1 variants that were selected in cell culture after serial passage of the NL4-3 strain in the presence of the compounds. After 24 passages (126 days) we isolated variants that were resistant to Suc-HSA (>27-fold) and Aco-HSA (37-fold), as compared with the wild-type NL4-3 virus. The binding of the NCA-resistant HIV strains to CD4+ MT-4 cells could no longer be inhibited by either Suc- or Aco-HSA. The emergence of mutations in the envelope gp120 of the resistant virus paralleled the emergence of the resistant phenotype. The Suc-HSA-resistant strain was 100-fold cross-resistant to the G quartet-containing oligonucleotide AR177 (Zintevir, an HIV-binding inhibitor), and partially cross-resistant to dextran sulfate, but remained sensitive to the bicyclam AMD3100 and the chemokine SDF-1alpha, which block HIV replication by interaction with the chemokine receptor CXCR4. Furthermore, neither Suc-HSA nor Aco-HSA inhibited the binding of monoclonal antibodies 12G5 and 2D7 (directed to CXCR4 and CCR5, respectively) in SUPT-1 cells or THP-1 cells. These results confirm that NCAs bind primarily to gp120 and do not interact directly with the HIV chemokine receptor but block the binding of the virus particles (through gp120) with CD4+ cells.
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PMID:Resistance of the human immunodeficiency virus to the inhibitory action of negatively charged albumins on virus binding to CD4. 1058 Apr 4

Human immunodeficiency virus type 1 (HIV-1) envelope glycoproteins interact with CD4 and chemokine receptors on T cells to deliver signals that trigger either activation, anergy, or apoptosis. However, the molecular mechanisms driving these responses remain poorly understood. In this study we demonstrate that apoptosis is induced upon HIV-1 envelope binding to the chemokine receptor CXCR4. Cells expressing a mutant form of CXCR4 with a C-terminal deletion were also sensitive to HIV-1 envelope-mediated apoptosis, indicating that the cytoplasmic tail of CXCR4 is not required to induce the apoptotic pathway. The specificity of this process was analyzed using several inhibitors of gp120-CD4-CXCR4 interaction. Monoclonal antibodies directed against the gp120-binding site on CD4 (ST4) and against CXCR4 (MAB173) prevented the apoptotic signal in a dose-dependent manner. The cell death program was also inhibited by SDF-1alpha, the natural ligand of CXCR4, and by suramin, a G protein inhibitor that binds with a high affinity to the V3 loop of HIV-1 gp120 envelope protein. These results highlight the role played by gp120-binding on CXCR4 to trigger programmed cell death. Next, we investigated the intracellular signal involved in gp120-induced apoptosis. This cell death program was insensitive to pertussis toxin and did not involve activation of the stress- and apoptosis-related MAP kinases p38(MAPK) and SAPK/JNK but was inhibited by a broad spectrum caspase inhibitor (z-VAD.fmk) and a relatively selective inhibitor of caspase 3 (z-DEVD.fmk). Altogether, our results demonstrate that HIV induces a caspase-dependent apoptotic signaling pathway through CXCR4.
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PMID:Caspase-dependent apoptosis of cells expressing the chemokine receptor CXCR4 is induced by cell membrane-associated human immunodeficiency virus type 1 envelope glycoprotein (gp120). 1070 41

Fusion of HIV with its host cell requires the interaction of the viral envelope glycoprotein 120 (gp120) with the chemokine receptor CXCR4 [T cell-tropic (T-tropic) or X4 HIV strains] or CCR5 [macrophage-tropic (M-tropic) or R5 HIV strains] followed by a 'spring-loaded' action of the glycoprotein 41 (gp41) that ensures fusion of the viral and cellular lipid membranes and permits the viral nucleocapsid to enter the cell. The overall fusion process can be blocked by a number of compounds. These include siamycin analogues, SPC 3 (a synthetic peptide derived from the V3 domain of gp120), pentafuside (T 20, DP 178) [a synthetic peptide corresponding to amino acid residues 127 to 162 of gp41], the betulinic acid derivative RPR 103611, TAK 779 (a low molecular weight non-peptide CCR5 antagonist) and a number of compounds (T 22, T 134, ALX40-4C, CGP64222 and AMD 3100) that are targeted at the CXCR4 receptor. In particular, the bicyclam AMD 3100 has proved highly potent and selective as a CXCR4 antagonist that blocks the infectivity of X4 HIV strains in the nanomolar concentration range. The proof-of-concept that fusion inhibitors should be able to suppress viral replication in vivo has been demonstrated with pentafuside. Pentafuside and AMD 3100 have now proceeded to phase II clinical trials.
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PMID:The emerging role of fusion inhibitors in HIV infection. 1072 72

In order to better define the role of HIV-related chemokines in human erythropoiesis we studied: A) the expression of chemokine receptors, both on human CD34(+) cells which include erythroid progenitors and on more mature erythroid cells; B) the functionality of these receptors by calcium flux, chemotaxis assay and phosphorylation of mitogen-activated protein kinases (MAPK) p42/44 (ERK1/ERK2) and AKT, and finally C) the influence of chemokines on BFU-E formation. We found that HIV-related chemokine receptor CXCR4, but not CCR5, is detectable on human CD34(+) BFU-E cells. CXCR4 surface expression decreased during erythroid maturation, although CXCR4 mRNA was still present in cells isolated from differentiated erythroid colonies. SDF-1, a CXCR4 ligand, induced calcium flux and phosphorylation of MAPK (p42/44) and AKT in CD34(+)KIT(+) bone marrow mononuclear cells which contain BFU-E, as well as chemotactic activity of both human CD34(+) BFU-E progenitors and erythroid cells isolated from day 2-6 BFU-E colonies. Responsiveness to SDF-1 decreased when the cells differentiated to the point of surface expression of the erythroid-specific marker Glycophorin-A. In contrast, the CCR5 ligands (macrophage inflammatory protein-1alpha [MIP-1alpha], MIP-1beta, and RANTES) did not activate calcium flux, MAPK and AKT phosphorylation or chemotaxis of CD34(+)KIT(+) cells or cells isolated from the BFU-E colonies. Interestingly, none of the chemokines tested in this study had any effect on BFU-E colony formation. In conclusion, only CXCR4 is functional, and its specific ligand SDF-1 may therefore play an important role in the homing and/or retention of early erythroid precursors in the bone marrow environment.
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PMID:The role of HIV-related chemokine receptors and chemokines in human erythropoiesis in vitro. 1074 85

HIV particles that use the chemokine receptor CXCR4 as a coreceptor for entry into cells (X4-HIV) inefficiently transmit infection across mucosal surfaces [1], despite their presence in seminal fluid and mucosal secretions from infected individuals [2] [3] [4]. In addition, although intestinal lymphocytes are susceptible to infection with either X4-HIV particles or particles that use the chemokine receptor CCR5 for viral entry (R5-HIV) during ex vivo culture [5], only systemic inoculation of R5-chimeric simian-HIV (S-HIV) results in a rapid loss of CD4(+) intestinal lymphocytes in macaques [6]. The mechanisms underlying the inefficient capacity of X4-HIV to transmit infection across mucosal surfaces and to infect intestinal lymphocytes in vivo have remained elusive. The CCR5 ligands RANTES, MIP-1alpha and MIP-1beta suppress infection by R5-HIV-1 particles via induction of CCR5 internalization, and individuals whose peripheral blood lymphocytes produce high levels of these chemokines are relatively resistant to infection [7] [8] [9]. Here, we show that the CXCR4 ligand stromal derived factor-1 (SDF-1) is constitutively expressed by mucosal epithelial cells at sites of HIV transmission and propagation. Furthermore, CXCR4 is selectively downmodulated on intestinal lymphocytes within the setting of prominent SDF-1 expression. We postulate that mucosally derived SDF-1 continuously downmodulates CXCR4 on resident HIV target cells, thereby reducing the transmission and propagation of X4-HIV at mucosal sites. Moreover, such a mechanism could contribute to the delayed emergence of X4 isolates, which predominantly occurs during the later stages of the HIV infection.
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PMID:Constitutive expression of stromal derived factor-1 by mucosal epithelia and its role in HIV transmission and propagation. 1074 78

Some colonic and neuronal cells which are CD4- but galactosyl ceramide-positive are susceptible to infection with HIV-1. We have previously shown that the T-cell tropic V3 loop of HIV-1 gp120 serves as a primary viral determinant for infectivity of CD4- neuronal cells. However, the nature of the V3 loop of HIV-1 needed for infection and the V3 loop's interaction with coreceptors on colonic epithelial cells have not been fully analyzed. By using HIV-1 molecular clones, we show that the T-cell tropic V3 domain is critical for HIV-1 infection of colonic HT-29 epithelial cells. Because T-cell tropic HIV-1 can use CXCR4 as a coreceptor in T cells, we set out to determine the role of CXCR4 during infection of HT-29 cells. Using reverse transcriptase-polymerase chain reaction (RT-PCR) and immunostaining, we show that these epithelial cells of colonic origin express the chemokine receptor CXCR4. Importantly, antibody against CXCR4 or a neutralizing antibody against HIV-1 gp120 V3 loop blocks T-cell tropic HIV-1 entry into HT-29 cells. These data indicate that the V3 loop of HIV-1 and the chemokine receptor CXCR4 are both critical for HIV-1 infection of colonic HT-29 epithelial cells. An HIV-1 T-tropic virus may be responsible for the infection of human colonic epithelial cells in vivo.
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PMID:T-tropic sequence of the V3 loop is critical for HIV-1 infection of CXCR4-positive colonic HT-29 epithelial cells. 1106 98

The alpha chemokine receptor CXCR4 and its only characterized chemokine ligand, stromal cell-derived factor-1 (SDF-1), are postulated to be important in the development of the B-cell arm of the immune system. In addition, CXCR4 is a critical coreceptor in support of viral entry by T-cell line tropic strains (X4) of the Human Immunodeficiency Virus Type 1 (HIV-1), viral variants which predominate in some infected individuals in end stage disease. SDF-1 can block X4-tropic HIV-1 infection of CD4+ target cells in vitro, and allelic variants of the human gene encoding SDF-1 in vivo correlate with delayed disease progression. Therefore, CXCR4 may be an appropriate target for therapeutic intervention in acquired immunodeficiency syndrome (AIDS), and knowledge of the pharmacology of SDF-1 binding to its cognate receptor will be important in the interpretation of these experiments. We report here a Kd derived using a competition binding assay of 4.5 nM for CXCR4 endogenously expressed on peripheral blood monocytes and T-cells. This affinity is similar to that which SDF-1 exhibits when binding to endogenous CXCR4 on an established immortal Jurkat T-cell line as well as recombinant CXCR4 transfected into Chinese Hamster Ovary (CHO) cells. We also demonstrate that the determined affinity of SDF-1 for CXCR4 is reflective of its ability to induce a CXCR4-mediated signal transduction in these different cell types. Furthermore, using Bordetella pertussis toxin, we observe that high affinity binding of SDF-1 to CXCR4 is independent of the G-protein coupled state of the receptor, as uncoupling of G-protein did not lead to the appearance of measurable low affinity SDF-1 binding sites. Moreover, binding affinity and receptor number were unaffected by uncoupling for both recombinant and endogenously expressed CXCR4. Thus, SDF-1 is novel among agonist ligands of G protein-coupled receptors in that it appears to have equal affinity for both the G protein-coupled and uncoupled states of CXCR4.
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PMID:The CXCR4 agonist ligand stromal derived factor-1 maintains high affinity for receptors in both Galpha(i)-coupled and uncoupled states. 1110 27

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