Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0021051 (immunodeficiency)
 71,517 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The human immunodeficiency virus (HIV-1) causes various hematopoietic abnormalities, with thrombocytopenia (TP) occurring in 30% of infected individuals. In the present study, we aimed to determine whether HIV-1 in the bone marrow of TP patients can infect primary megakaryocytes in vitro, which may contribute to the development of thrombocytopenia. We amplified the V3 loop of HIV-1 envelope from the bone marrow of TP and non-TP patients and constructed recombinant viruses. We demonstrate that the bone marrow of TP and non-TP patients contained R5 strains, whereas X4 strains were present only in the bone marrow of TP patients. Furthermore, HIV-1 from the bone marrow of TP and non-TP patients infected megakaryocytes to similar levels, suggesting that the V3 loop of HIV-1 may not contain the viral determinants of HIV-associated TP. Chemokine receptor analysis determined that CD34+-cell-derived megakaryocytes express CD4, CXCR4, and CCR5 and are productively infected by both X4 and R5 HIV-1 isolates. Finally, we showed that CD34+-cell-derived megakaryocytes express the chemokine receptor CCR3.
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PMID:Productive infection of CD34+-cell-derived megakaryocytes by X4 and R5 HIV-1 isolates. 1072

Primary simian immunodeficiency virus (SIV) isolated from sooty mangabey (SIVsm [n = 6]), stumptail (SIVstm [n = 1]), mandrill (SIVmnd [n = 1]), and African green (SIVagm [n = 1]) primates were examined for their ability to infect human cells and for their coreceptor requirements. All isolates infected human peripheral blood mononuclear cells (PBMCs) from a CCR5(+/+) donor, and seven of eight isolates tested also infected CCR5(-/-) PBMCs. Analysis of coreceptor utilization using GHOST and U87 cell lines revealed that all of the isolates tested used CCR5 and the orphan receptors STRL33 and GPR15. Coreceptors such as CCR2b, CCR3, CCR8, and CX3CR1 were also utilized by some primary SIV isolates. More importantly, we found that CXCR4 was used as a coreceptor by the SIVstm, the SIVagm, and four of the SIVsm isolates in GHOST and U87 cells. These data suggest that primary SIV isolates from diverse primate species can utilize CXCR4 for viral entry, similar to what has been described for human immunodeficiency viruses.
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PMID:Simian immunodeficiency viruses of diverse origin can use CXCR4 as a coreceptor for entry into human cells. 1082 78

We describe a small molecule chemokine receptor antagonist, UCB35625 (the trans-isomer J113863 published by Banyu Pharmaceutical Co., patent WO98/04554), which is a potent, selective inhibitor of CCR1 and CCR3. Nanomolar concentrations of UCB35625 were sufficient to inhibit eosinophil shape change responses to MIP-1alpha, MCP-4, and eotaxin, while greater concentrations could inhibit the chemokine-induced internalization of both CCR1 and CCR3. UCB35625 also inhibited the CCR3-mediated entry of the human immunodeficiency virus-1 primary isolate 89.6 into the glial cell line, NP-2 (IC(50) = 57 nm). Chemotaxis of transfected cells expressing either CCR1 or CCR3 was inhibited by nanomolar concentrations of the compound (IC(50) values of CCR1-MIP-1alpha = 9.6 nm, CCR3-eotaxin = 93.7 nm). However, competitive ligand binding assays on the same transfectants revealed that considerably larger concentrations of UCB35625 were needed for effective ligand displacement than were needed for the inhibition of receptor function. Thus, it appears that the compound may interact with a region present in both receptors that inhibits the conformational change necessary to initiate intracellular signaling. By virtue of its potency at the two major eosinophil chemokine receptors, UCB35625 is a prototypic therapy for the treatment of eosinophil-mediated inflammatory disorders, such as asthma and as an inhibitor of CCR3-mediated human immunodeficiency virus-1 entry.
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PMID:A small molecule antagonist of chemokine receptors CCR1 and CCR3. Potent inhibition of eosinophil function and CCR3-mediated HIV-1 entry. 1085 42

Activation of beta-chemokine receptors, co-receptors for human immunodeficiency virus type-1 (HIV-1), stimulates movement and secretion in microglia, possibly through a Ca(2+)-dependent mechanism. We studied chemokine activation of Ca(2+) signaling processes in microglia. Human fetal microglia were grown in primary culture and chemokine-induced increases in intracellular calcium concentration ([Ca(2+)](i)) were measured in single cells using indo-1-based microfluorimetry. Application of 50 ng/ml regulated on activation, normal T expressed and secreted (RANTES; 120 s) evoked responses in 26% of the microglia (187/719 cells). [Ca(2+)](i) increased from a basal level of 66+/-6 nM to peak at 268+/-23 nM (n=187). Chemokine-evoked responses rapidly desensitized as indicated by the rapid return to basal [Ca(2+)](i) levels in the maintained presence of RANTES. The removal of extracellular Ca(2+) or stimulation in the presence of Ni(2+) (2mM) or La(3+) (100 microM) blocked the RANTES-elicited [Ca(2+)](i) increase. The L-type calcium channel antagonist nimodipine (10 microM) inhibited the RANTES-mediated increase in [Ca(2+)](i) by 80+/-16%. Thus, the RANTES-evoked calcium transient appears to result from Ca(2+) influx with little if any release from intracellular stores. Application of gp120(clade) (E) and gp120(CM235) (50 ng/ml) neither mimicked nor antagonized the RANTES-evoked response. Application of 50 ng/ml eotaxin (120 s) evoked an increase in [Ca(2+)](i) in 13% of the human microglia in culture (61/469 cells). The HIV-1 regulatory protein Tat (50 ng/ml) increased the [Ca(2+)](i) in a subset of eotaxin-responsive cells (16/30). The L-type calcium channel antagonist nimodipine (3 microM) inhibited eotaxin- and Tat-mediated increases in [Ca(2+)](i) by 88+/-6% and 93+/-6%, respectively. Thus, activation of CCR3 appears to evoke Ca(2+) influx through L-type Ca(2+) channels.These results indicate that beta-chemokines, RANTES and eotaxin, activate a nimodipine sensitive Ca(2+) influx pathway in human fetal microglia. HIV-1 Tat protein mimicked chemokine-mediated Ca(2+) signaling and may modulate the migratory and secretory responses of microglia.
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PMID:Beta-chemokines and human immunodeficiency virus type-1 proteins evoke intracellular calcium increases in human microglia. 1085 25

We have used coreceptor-targeted inhibitors to investigate which coreceptors are used by human immunodeficiency virus type 1 (HIV-1), simian immunodeficiency viruses (SIV), and human immunodeficiency virus type 2 (HIV-2) to enter peripheral blood mononuclear cells (PBMC). The inhibitors are TAK-779, which is specific for CCR5 and CCR2, aminooxypentane-RANTES, which blocks entry via CCR5 and CCR3, and AMD3100, which targets CXCR4. We found that for all the HIV-1 isolates and all but one of the HIV-2 isolates tested, the only relevant coreceptors were CCR5 and CXCR4. However, one HIV-2 isolate replicated in human PBMC even in the presence of TAK-779 and AMD3100, suggesting that it might use an undefined, alternative coreceptor that is expressed in the cells of some individuals. SIV(mac)239 and SIV(mac)251 (from macaques) were also able to use an alternative coreceptor to enter PBMC from some, but not all, human and macaque donors. The replication in human PBMC of SIV(rcm) (from a red-capped mangabey), a virus which uses CCR2 but not CCR5 for entry, was blocked by TAK-779, suggesting that CCR2 is indeed the paramount coreceptor for this virus in primary cells.
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PMID:Use of inhibitors to evaluate coreceptor usage by simian and simian/human immunodeficiency viruses and human immunodeficiency virus type 2 in primary cells. 1088 29

Because helminth infections and human immunodeficiency virus (HIV) coexist in areas where the spread of AIDS is most dramatic, their in vitro interaction was explored. Cryopreserved peripheral blood mononuclear cells (PBMC) from patients with filarial infections (n=24) and from unexposed control subjects (n=12) were depleted of CD8 T cells and were infected with macrophage (M)- and T cell-tropic viruses. A trend toward increased HIV replication in PBMC from filaria-infected patients was observed. Furthermore, PBMC from 6 filaria-infected patients before antifilarial treatment were significantly more susceptible to replication of M-tropic virus than their posttreatment PBMC (P=.03). No intergroup differences were found in the surface expression of HLA-DR, CD25, CCR5, CXCR4, CCR3 on CD4 T cells, or monocytes before infection. PBMC from filaria-infected patients produced less RANTES (P=.02) but more intracellular interleukin-4 than those of control subjects. Thus, PBMC from persons with filarial infections appear to have enhanced susceptibility to HIV-1 infection mediated by an undetermined mechanism.
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PMID:Filarial infections increase susceptibility to human immunodeficiency virus infection in peripheral blood mononuclear cells in vitro. 1106 60

The evolution of human immunodeficiency virus type 1 infection is associated with a shift in the target cell population, driven by variability in coreceptor utilization resulting from diversity in env. To elucidate the potential consequences of these changes for Env-mediated fusion over the course of AIDS, we examined the biological properties of serial viral isolates and determined coreceptor utilization by the products of env cloned from two individuals, followed from the detection of seroconversion throughout the course of their infection. One had a typical course, and the other had an accelerated progression. Early isolates were non-syncytium inducing, and the corresponding Env exclusively utilized CCR5, whereas Env from late phases of infection showed restricted utilization of CXCR4 in both patients. Env from subject SC24, who had a standard progression, demonstrated multitropism, manifested by utilization of CCR3, CXCR4, and CCR5 in the intervening period. In contrast, Env from patient SC51, who experienced early conversion to the syncytium-inducing phenotype, developed dualtropic coreceptor utilization of CCR5 and CXCR4. Genetic analysis of env from each isolate revealed that those with an X4 phenotype formed a distinct subcluster within each subject. Analysis of chimeras constructed from R5 and multispecific env from patient SC24 demonstrated that while the V3 domain played a dominant role in determining coreceptor utilization, sequences in the V4-V5 region also contributed to the latter phenotype. Immunoprecipitation experiments confirmed that the hybrid Env proteins were expressed at similar levels. These experiments demonstrate that progression from the R5 to X4 phenotype may occur through a multi- or dual-tropic intermediate and that multiple domains contribute to this process.
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PMID:Evolution of the human immunodeficiency virus type 1 envelope during infection reveals molecular corollaries of specificity for coreceptor utilization and AIDS pathogenesis. 1109 Jan 86

Although selected chemokines act as natural inhibitors of human immunodeficiency virus (HIV) infection, their inherent proinflammatory activity may limit a therapeutic use. To elucidate whether the antiviral and signaling functions of RANTES can be dissociated, several recombinant analogues mutated at the N terminus were generated and functionally compared with the wild-type (WT) molecule, as well as with three previously described mutants. Substitution of selected residues within the N-terminal region caused a marked loss of antiviral potency. By contrast, two unique analogues (C1.C5-RANTES and L-RANTES) exhibited an increased antiviral activity against different CXCR4-negative HIV-1 isolates grown in primary mononuclear cells or in macrophages. This enhanced HIV-blocking activity was associated with an increased binding affinity for CCR5. Both C1.C5-RANTES and L-RANTES showed a dramatically reduced ability to trigger intracellular calcium mobilization via CCR3 or CCR5, while potently antagonizing the action of the WT chemokine. By contrast, two previously described analogues (RANTES(3-68) and AOP-RANTES) maintained a WT ability to trigger CCR5-mediated signaling, while a third one (RANTES(9-68)) showed a dramatic loss of antiviral activity. These data demonstrate that the antiviral and signaling functions of RANTES can be uncoupled, opening new perspectives for the development of chemokine-based therapeutic approaches for HIV infection.
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PMID:Enhancement of the HIV-1 inhibitory activity of RANTES by modification of the N-terminal region: dissociation from CCR5 activation. 1109 34

More than 10 G protein-coupled receptors (GPCRs) have been reported to act as coreceptors for entry of human and simian immunodeficiency viruses (HIV and SIV). We investigated the utilization of six GPCRs as coreceptors by T-cell-line-adapted HIV-2 strains (CBL-20, CBL-21, CBL-23, GH-1, ROD, and SBL6669) and SIV strains (SIVagmTYO-1, SIVmac251, and SIVmndGB-1). NP-2/CD4 cells were transduced with CCR3, CCR5, CCR8, CXCR4, GPR1, or APJ, and examined for susceptibilities to cell-free HIV/SIV. HIV-2 strains were grouped into two types by their coreceptor usage. The first group, CBL-20 and CBL-21, used CXCR4 exclusively; the other four strains used a few or all of the six coreceptors. These strains could further infect CD4-negative NP-2/CXCR4 or NP-2/CCR5 cells in the presence (all strains) or absence (SBL6669 and ROD strains) of soluble CD4. SIVagm and SIVmnd infected NP-2/CD4/GPR1 cells. The coreceptors CCR3, CCR8, GPR1, and APJ did not mediate the CD4-independent infection. Although HIV-2ROD and SIVmnd infected both NP-2/CD4/CXCR4 and NP-2/CD4/CCR5 cells, only CXCR4 and CCR5, respectively, were used in CD4-independent infection. Binding of virions to CD4-negative cells occurred at 4 degrees C. These findings suggest that there may be a correlation between the promiscuous use of coreceptors by HIV-2/SIV strains and their ability to infect CD4-negative cells.
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PMID:CD4-Dependent and CD4-independent utilization of coreceptors by human immunodeficiency viruses type 2 and simian immunodeficiency viruses. 1111 2

The CXC chemokine receptor CXCR4 was the first molecule identified as a coreceptor working in conjunction with CD4 to mediate cellular entry for the human immunodeficiency virus (HIV-1). Since that original discovery, 11 other seven-mtransmembrane domain molecules, many of which are chemokine receptors, have been shown to facilitate HIV entry into cells. These include CCR5, CCR3, CCR2, CCR1, CCR8, CX3CR1, STRL33 (BONZO), GPR15 (BOB), GPR1, US28, and APJ. In studies done by this and other labs, CCR3, CCR5, and CXCR4 have been identified in CNS microglia and several laboratories, including ours, have shown that CXCR4 is expressed in neurons. Neuronal expression of CCR2, CCR3, and CCR5 has been less consistent. We performed a semiquantitative immunohistochemical analysis of the expression of CCR2, CCR3, CCR5, and CXCR4 in 23 regions of the brain and in two sections of the spinal cord. Hippocampal neurons were positive for CCR2, CCR3, and CXCR4, but not for CCR5. In other regions of the brain, neurons, and glial cells reacted with anti-CCR2, anti-CCR3, and anti-CXCR4 antibodies, whereas only glial cells (primarily microglia) were positive for CCR5. The areas of highest expression, however, seem to be subcortical regions and the limbic system. The limbic system plays a key role in memory, and the presence of CXCR4-which can bind the viral envelope protein gp120-min a subset of neurons from this system may play a role in the development of HIV-related dementia.
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PMID:Immunohistochemical analysis of CCR2, CCR3, CCR5, and CXCR4 in the human brain: potential mechanisms for HIV dementia. 1111 60


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