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Query: UMLS:C0019693 (HIV)
 170,526 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Protection against SIV or HIV infection requires specific antibodies and T-cell immune responses. However, a complementary mechanism may be involved, in which CD8-suppressor factors (CD8-SF) and the constitutive beta-chemokines may prevent the virus binding and replicating. Indeed, there is evidence that targeted iliac lymph node (TILN) immunisation with SIVgp120 and p27 or xenoimmunisation with SIV grown in human T-cells generates CD8-SF, RANTES, MIP-1alpha and MIP-1beta which are significantly correlated with protection from SIV infection by the rectal mucosal or intravenous route, respectively. Inhibition of SIV replication in vitro is dependent on the concentration of beta-chemokines generated by immunisation. The critical level for inhibition of SIV replication appears to be higher for rectal mucosal than intravenous challenge by SIV. The mechanism of protection in vivo has not been elucidated but it is likely that the beta-chemokines bind to CCR5 coreceptors which are internalised. Thus, CCR5 coreceptors are either blocked or not expressed on the cell surface for SIV to bind and infect.
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PMID:CD8-suppressor factor and beta-chemokine function as a complementary mechanism to cognate immunity. 1020 51

Macrophage (M)-tropic HIV-1 isolates use the beta-chemokine receptor CCR5 as a coreceptor for entry, while T cell line-adapted (TCLA) strains use CXCR4 and dual-tropic strains can use either CCR5 or CXCR4. To investigate the viral determinants involved in choice of coreceptor, we used a fusion assay based on the infection of CD4+ HeLa cells that express one or both coreceptors with Semliki Forest virus (SFV) recombinants expressing the native HIV-1 gp160 of a primary M-tropic isolate (HIV-1BX08), a TCLA isolate (HIV-1LAI), or a dual-tropic strain (HIV-1MN). We examined whether the V3 region of these glycoproteins interacts directly with the corresponding coreceptors by assaying coreceptor-dependent cell-to-cell fusion mediated by the different recombinants in the presence of various synthetic linear peptides. Synthetic peptides corresponding to different V3 loop sequences blocked syncytium formation in a coreceptor-specific manner. Synthetic V2 peptides were also inhibitory for syncytium formation, but showed no apparent coreceptor specificity. A BX08 V3 peptide with a D320 --> R substitution retained no inhibitory capacity for BX08 Env-mediated cell-to-cell fusion, but inhibited LAI Env-mediated fusion as efficiently as the homologous LAI V3 peptide. The same mutation engineered in the BX08 env gene rendered it able to form syncytia on CD4+CXCR4+CCR5-HeLa cells and susceptible to inhibition by SDF-1alpha and MIP-1beta. Other substitutions tested (D320 --> Q/D324 --> N or S306 --> R) exhibited intermediate effects on coreceptor usage. These results underscore the importance of the V3 loop in modulating coreceptor choice and show that single amino acid modifications in V3 can dramatically modify coreceptor usage. Moreover, they provide evidence that linear V3 loop peptides can compete with intact cell surface-expressed gp120/gp41 for CCR5 or CXCR4 interaction.
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PMID:Role of the HIV type 1 glycoprotein 120 V3 loop in determining coreceptor usage. 1035 69

Chemokines play diverse roles in inflammatory and non-inflammatory situations via activation of heptahelical G-protein-coupled receptors. Also, many chemokine receptors can act as cofactors for cellular entry of human immunodeficiency virus (HIV) in vitro. CCR5, a receptor for chemokines MIP-1alpha (LD78alpha), MIP-1beta, RANTES, and MCP2, is of particular importance in vivo as polymorphisms in this gene affect HIV infection and rate of progression to AIDS. Moreover, the CCR5 ligands can prevent HIV entry through this receptor and likely contribute to the control of HIV infection. Here we show that a non-allelic isoform of human MIP-1alpha (LD78alpha), termed LD78beta or MIP-1alphaP, has enhanced receptor binding affinities to CCR5 (approximately 6-fold) and the promiscuous beta-chemokine receptor, D6 (approximately 15-20-fold). We demonstrate that a proline residue at position 2 of MIP-1alphaP is responsible for this enhanced activity. Moreover, MIP-1alphaP is by far the most potent natural CCR5 agonist described to date, and importantly, displays markedly higher HIV1 suppressive activity than all other human MIP-1alpha isoforms examined. In addition, while RANTES has been described as the most potent inhibitor of CCR5-mediated HIV entry, MIP-1alphaP was as potent as, if not more potent than, RANTES in HIV-1 suppressive assays. This property suggests that MIP-1alphaP may be of importance in controlling viral spread in HIV-infected individuals.
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PMID:LD78beta, a non-allelic variant of human MIP-1alpha (LD78alpha), has enhanced receptor interactions and potent HIV suppressive activity. 1036 78

Human immunodeficiency virus type 1 (HIV-1) requires, in addition to CD4, coreceptors of the CC or CXC chemokine families for productive infection of T cells and cells of the monocyte-macrophage lineage. Based on the hypothesis that coreceptor expression on alveolar macrophages (AM) may influence HIV-1 infection of AM in the lung, this study analyzes the expression and utilization of HIV-1 coreceptors on AM of healthy individuals. AM were productively infected with five different primary isolates of HIV-1. Levels of surface expression of CCR5, CXCR4, and CD4 were low compared to those of blood monocytes, but CCR3 was not detectable. mRNA for CCR5, CXCR4, CCR2, and CCR3 were all detectable, but to varying degrees and with variability among donors. Expression of CCR5, CXCR4, and CCR2 mRNA was downregulated following stimulation with lipopolysaccharide (LPS). In contrast, secretion of the chemokines RANTES, MIP-1alpha, and MIP-1beta was upregulated with LPS stimulation. Interestingly, HIV-1 replication was diminished following LPS stimulation. Infection of AM with HIV-1 in the presence of the CC chemokines demonstrated blocking of infection. Together, these studies demonstrate that AM can be infected by a variety of primary HIV-1 isolates, AM express a variety of chemokine receptors, the dominant coreceptor used for HIV entry into AM is CCR5, the expression of these receptors is dependent on the state of activation of AM, and the ability of HIV-1 to infect AM may be modulated by expression of the chemokine receptors and by chemokines per se.
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PMID:Expression and use of human immunodeficiency virus type 1 coreceptors by human alveolar macrophages. 1036 38

Central nervous system (CNS) involvement is a prominent feature of human immunodeficiency virus (HIV-1) infection. Monocytes and CD4+ T cells traverse the blood brain barrier (BBB), and serve as vehicles for the virus and perpetrators for brain pathology by their production of neurotoxins. In the present study cerebrospinal fluid (CSF) samples from HIV-1-infected patients were analyzed for the presence of chemotactic factors. All 36 CSF samples from the patients were positive for the CXC chemokine interferon-gamma inducible protein (IP-10), which was not detected in CSF samples of 14 controls. The IP-10 concentrations were higher in HIV-1-infected patients with HIV-1 associated neurologic disorders than in those without neurological deficits. In contrast to IP-10, other chemotactic factors including the CC chemokines MCP-1, MIP-1alpha, MIP-1beta and RANTES and the cytokines IL-15 and IL-16 were either not detected or increased in only less than 30% of the patients. Unlike the CSF samples of controls, all CSF samples from HIV-1-infected patients induced chemotaxis of T cells activated with IL-2. The significance of IP-10 as a T cell chemotactic cytokine in HIV-1-infected CSF is shown by (1) the correlation of the IP-10 levels with the extent of T cell chemotaxis, (2) the neutralization of T cell chemotaxis by anti-IP-10 antibodies and (3) the correlation of the chemotactic response of CSF samples on activated T cells and the CSF white cell count in the patients. Our data provide evidence that IP-10 contributes to the accumulation of activated T cells in the CSF compartment in HIV-1-infected individuals.
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PMID:Identification of a T cell chemotactic factor in the cerebrospinal fluid of HIV-1-infected individuals as interferon-gamma inducible protein 10. 1037 81

CCR5 is the major coreceptor for macrophage-tropic human immunodeficiency virus type I (HIV-1). For most G-protein-coupled receptors that have been tested so far, the disulfide bonds linking together the extracellular loops (ECL) are required for maintaining the structural integrity necessary for ligand binding and receptor activation. A natural mutation affecting Cys20, which is thought to form a disulfide bond with Cys269, has been described in various human populations, although the consequences of this mutation for CCR5 function are not known. Using site-directed mutagenesis, we mutated the four extracellular cysteines of CCR5 singly or in combination to investigate their role in maintaining the structural conformation of the receptor, its ligand binding and signal transduction properties, and its ability to function as a viral coreceptor. Alanine substitution of any single Cys residue reduced surface expression levels by 40-70%. However, mutation of Cys101 or Cys178, predicted to link ECL1 and ECL2 of the receptor, abolished recognition of CCR5 by a panel of conformation sensitive anti-CCR5 antibodies. The effects of the mutations on receptor expression and conformation were partially temperature-sensitive, with partial restoration of receptor expression and conformation achieved by incubating cells at 32 degrees C. All cysteine mutants were unable to bind detectable levels of MIP-1beta, and did not respond functionally to CCR5 agonists. Surprisingly, all cysteine mutants did support infection by R5 strains of HIV, though at reduced levels. These results indicate that both disulfide bonds of CCR5 are necessary for maintaining the structural integrity of the receptor necessary for ligand binding and signaling. Env binding and the mechanisms of HIV entry appear much less sensitive to alterations of CCR5 conformation.
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PMID:Extracellular cysteines of CCR5 are required for chemokine binding, but dispensable for HIV-1 coreceptor activity. 1038 87

The chemokine receptor CCR5 has been found to play a key role in early infection with macrophage-tropic isolates of HIV-1 and CCR5 deficiency is associated with a relative resistance to HIV-1 infection. In this context, we studied the regulation of CCR5 gene expression by cytokines, and in particular, interleukin (IL)-10 in human monocytes. CCR5 mRNA was rapidly up-regulated by exposure of monocytes to graded concentrations of IL-10, with near maximal stimulation with 10 ng/ml. The effect was rapid, being detectable as early as 1 h and maximal between 2 and 4 h of treatment. Pretreatment of monocytes with actinomycin D prevented the IL-10-induced effect, suggesting a transcriptional mechanism for CCR5 up-regulation by IL-10. Protein expression of CCR5 was also enhanced by IL-10, as indicated by a 3-fold increase in anti-CCR5 antibody labeling of monocytes treated for 20 h with IL-10. Increased surface expression of CCR5 persisted at 48 h of treatment. Moreover, IL-10-treated monocytes responded with augmented intracellular Ca++ mobilization and enhanced (3-4-fold) chemotaxis in response to the CCR5 ligand MIP-1beta(25 ng/ml). Taken together, our data indicate that IL-10 can modulate CCR5 expression and function. This can constitute a potentially important regulatory mechanism which can affect not only responses during inflammation, but also susceptibility to HIV-1 infection.
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PMID:IL-10 up-regulates CCR5 gene expression in human monocytes. 1039 58

HIV-1 glycoprotein gp120 induces injury and apoptosis in rodent and human neurons in vitro and in vivo and is therefore thought to contribute to HIV-associated dementia. In addition to CD4, different gp120 isolates bind to the alpha- or beta-chemokine receptors CXCR4 and CCR5, respectively. These and other chemokine receptors are on brain macrophages/microglia, astrocytes, and neurons. Thus, apoptosis could occur via direct interaction of gp120 with neurons, indirectly via stimulation of glia to release neurotoxic factors, or via both pathways. Here we show in rat cerebrocortical cultures that recapitulate the type and proportion of cells normally found in brain, i.e., neurons, astrocytes, and macrophages/microglia, that the beta-chemokines RANTES (regulated on activation, normal T cell expressed and secreted) and macrophage inflammatory protein (MIP-1beta) protect neurons from gp120SF2-induced apoptosis. The gp120SF2 isolate prefers binding to CXCR4 receptors, similar to the physiological alpha-chemokine ligands, stromal cell-derived factor (SDF)-1alpha/beta. SDF-1alpha/beta failed to prevent gp120SF2 neurotoxicity, and in fact also induced neuronal apoptosis. We could completely abrogate gp120SF2-induced neuronal apoptosis with the tripeptide TKP, which inhibits activation of macrophages/microglia. In contrast, TKP or depletion of macrophages/microglia did not prevent SDF-1 neurotoxicity. Inhibition of p38 mitogen-activated protein kinase ameliorated both gp120SF2- and SDF-1-induced neuronal apoptosis. Taken together, these results suggest that gp120SF2 and SDF-1 differ in the cell type on which they stimulate CXCR4 to induce neuronal apoptosis, but both ligands use the p38 mitogen-activated protein kinase pathway for death signaling. Moreover, gp120SF2-induced neuronal apoptosis depends predominantly on an indirect pathway via activation of chemokine receptors on macrophages/microglia, whereas SDF-1 may act directly on neurons or astrocytes.
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PMID:Chemokines and activated macrophages in HIV gp120-induced neuronal apoptosis. 1039 74

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

Vgamma9Vdelta2 T lymphocytes are broadly reactive against various intracellular pathogens and display both lytic and proliferative responses to human immunodeficiency virus (HIV)-infected cells. HIV infection of peripheral blood mononuclear cell cultures led to absolute increases in Vgamma9Vdelta2 T cells accompanied by decreased p24 levels. Strong gammadelta T cell activation with nonpeptidic mycobacterial phosphoantigens (TUBAg1 extract or synthetic isopentenyl pyrophosphate) resulted in potent inhibition of HIV replication through soluble released factors. Subsequent analyses showed that phosphoantigen-activated gammadelta T cells produced substantial amounts of beta-chemokines (macrophage inflammatory protein [MIP]-1alpha, MIP-1beta, and regulated-on-activation, normal T-cell-expressed and -secreted beta-chemokine [RANTES]), which represent the natural ligand for the CCR5 HIV coreceptor. Accordingly, anti-beta-chemokine antibodies neutralized the inhibition of monocytotropic HIV strains by gammadelta T cell-released factors. Moreover, a T-tropic HIV strain using the CXCR4 coreceptor for virus entry was potently inhibited. Together, these data reveal that phosphoantigen-activated gammadelta T cells are an important source of CC chemokines and may suppress HIV replication through cell-released antiviral factors.
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PMID:Phosphoantigen-reactive Vgamma9Vdelta2 T lymphocytes suppress in vitro human immunodeficiency virus type 1 replication by cell-released antiviral factors including CC chemokines. 1043 80


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