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

The chemokine receptor CCR5 plays a key role in the CD4-dependent entry of human and simian immunodeficiency viruses into target cells. We have mapped the interaction sites on CCR5 for a number of novel anti-CCR5 monoclonal antibodies and have used these to study the role of the CCR5 N-terminal ectodomain in viral entry and to demonstrate differential CCR5 epitope expression on different cell types. Deletions of the CCR5 amino terminal domain or substitution with equivalent regions from other chemokine receptors did not affect cell surface expression or reactivity with loop-specific antibodies, suggesting that the loop regions remained conformationally intact. Exchanges of the amino terminal segment of CCR5 with the equivalent domains of CCR1, CCR2, and CXCR4 did not significantly affect infection with virus pseudotyped with envelope glycoproteins (Envs) from HIV-2 and SIV, but substitution with the CXCR4 sequence abrogated entry mediated by Env from HIV-1. In contrast, deletion of the amino terminus abrogated CCR5 receptor activity for all viral Envs examined. These data indicate that the amino terminus of CCR5 has an essential role in entry mediated by diverse viral Envs but that the sequence requirements are more relaxed for the HIV-2 and SIV Envs compared to the HIV-1 Env examined. This suggests that different viral Envs make distinct and specific interactions with the amino terminus of CCR5. Viral Env utilization of CCR5 expressed on 293-T cells does not always correlate with the cellular tropism of the virus, and one possible explanation is that Env-accessible interaction sites on CCR5 differ on different cell types. We therefore analyzed binding of several anti-CCR5 monoclonal antibodies to cell lines and primary cells that express this chemokine receptor and found that whereas all antibodies bound to CCR5-transfected 293T cells, several did not bind to PBMC. The results suggest that CCR5 undergoes cell type specific structural modifications which may affect interaction with different HIV and SIV envelope glycoproteins.
 ...
PMID:The amino terminus of human CCR5 is required for its function as a receptor for diverse human and simian immunodeficiency virus envelope glycoproteins. 972 Dec 44

The effect of macrophage (M)-tropic and T cell line (T)-tropic human immunodeficiency virus type 1 (HIV-1) infection on antigen-specific CD4 cytotoxic T lymphocytes (CTLs) has been studied using a CD4 CTL line specific for a peptide from influenza B virus hemagglutinin. In the absence of antigen presentation, the production of CC chemokines was low. Both the M-tropic HIV-1 strain (HIV-1AD) and the T-tropic HIV-1 strain (HIV-1LAI) established productive infections in the CD4 CTLs, decreasing antigen-specific cytotoxicity. Peptide presented to the CD4 CTLs increased their secretion of RANTES and MIP-1beta, suppressed M-tropic HIV-1 replication, downmodulated CCR5 expression, and preserved CTL recognition. The suppression of M-tropic HIV-1 replication and downmodulation of the CCR5 receptor likely resulted from CC chemokine secretion since antibodies to CC chemokines restored M-tropic HIV-1 replication. Antigen presentation did not protect CD4 CTLs from T-tropic HIV-1 infection or preserve their CTL recognition. Thus, these CD4 CTLs do not make suppressor factors that inhibit the T-tropic HIV-1LAI isolate. The results indicate that these CD4 CTLs can either harbor or suppress M-tropic HIV-1 infection, depending on whether antigen is present. CD4 CTLs might therefore provide some protection in the early stages of HIV-1 infection when M-tropic isolates are present.
 ...
PMID:Human immunodeficiency virus type 1 infection of antigen-specific CD4 cytotoxic T lymphocytes. 982 17

We have shown that the binding of simian immunodeficiency virus (SIV) to Jurkat T cells expressing CD4 receptor strongly induces mitogen-activated protein (MAP) kinase kinase (MEK) and extracellular signal-regulated kinases 1 and 2 (ERK1/2) and only weakly induces p38 MAP kinase and c-Jun N-terminal kinase (JNK). Similarly, T-tropic NL4-3 virus, which uses both CD4 and CXCR4 receptors for entry, stimulated in these cells the MEK/ERK MAP kinase (MAPK) pathway in a CD4 receptor-dependent manner (Popik and Pitha, 1998). In contrast, both macrophage-tropic SIVmac316 and T cell-tropic SIVmac239, which in addition to CD4 require CCR5 coreceptor for entry, significantly enhanced early MEK/ERK, p38 MAPK, and JNK signaling in Jurkat cells expressing constitutively or transiently the CCR5 receptor. Together, this study provides the evidence that viruses using CXCR4 or CCR5 receptors for entry may differentially use signaling properties of their specific coreceptors to stimulate MAP kinase cascades. In addition, although SIVmac239 and SIVmac316 use different structural domains of the CCR5 receptor for entry, both viruses stimulate early phosphorylation of MEK, ERK, p38, and JNK independently of their tropism and replication.
 ...
PMID:Early activation of mitogen-activated protein kinase kinase, extracellular signal-regulated kinase, p38 mitogen-activated protein kinase, and c-Jun N-terminal kinase in response to binding of simian immunodeficiency virus to Jurkat T cells expressing CCR5 receptor. 987 30

Despite being able to use the Bonzo coreceptor as efficiently as CCR5 in transfected cells, pediatric human immunodeficiency virus type 1 isolate P6 was unable to replicate in peripheral blood mononuclear cells (PBMC) lacking the CCR5 receptor. Furthermore, its replication in wild-type PBMC was completely inhibited by inhibitors of CCR5-mediated entry. Similarly, maternal isolate M6 could use CCR5, CXCR4, Bonzo, and other coreceptors in transfected cells but was completely sensitive to inhibitors of CCR5- and CXCR4-mediated entry when grown in PBMC. The ability of these viruses to use coreceptors in addition to CCR5 and CXCR4 in vitro was, therefore, irrelevant to their drug sensitivity in primary cells. We argue that CCR5 and CXCR4 should remain the primary targets for antiviral drug development, pending strong evidence to the contrary.
 ...
PMID:Will multiple coreceptors need to be targeted by inhibitors of human immunodeficiency virus type 1 entry? 1007

High-molecular-weight dextran sulfate (HMDS) inhibits infection of CD4+ lymphocytes by T-cell (T)-tropic human immunodeficiency virus (HIV) isolates, but augments replication of macrophage (M)-tropic isolates in primary human macrophages and phorbol myristate acetate (PMA)-differentiated THP-1 monocytic cells. To address the mechanism responsible for HMDS-mediated increases in HIV replication in macrophages, we analyzed the interaction between HMDS and functional domains of gp120 on the surface of PMA-differentiated THP-1 cells infected with M-tropic HIV isolates. Immunofluorescence staining of the infected cells revealed that HMDS inhibited the binding of monoclonal antibodies (mAbs) directed to the V3 and C4 domains of gp120, but augmented the binding of three neutralizing antibodies directed to the V2 region of gp120. The extent of HMDS-mediated changes within the V2 loop of gp120 was associated with increased virus binding and replication in PMA-differentiated THP-1 cells and primary macrophages. The effect was dependent on expression of the CCR5 receptor and was inhibited by the beta-chemokine RANTES. Results of this study suggest that HMDS-mediated increases in HIV infection in macrophages are associated with conformational changes within the V2 region of gp120 and enhanced interaction between gp120 and the CCR5 coreceptor on the target cell.
 ...
PMID:Enhanced human immunodeficiency virus infection in macrophages by high-molecular-weight dextran sulfate is associated with conformational changes of gp120 and expression of the CCR5 receptor. 1033 39

The feline immunodeficiency virus (FIV) causes a disease in cats similar in clinical presentation and disease progression to that of HIV and AIDS. It is now known that, for HIV infection, as well as primary binding of virus to the CD4 receptor, entry and infection of cells requires coreceptors which are members of the chemokine group of G-protein coupled receptors. Because of the similarity of HIV and FIV, we hypothesised that coreceptors are required for the entry and infection of cells by FIV. Using a feline cDNA library derived from a feline IL-2 sensitive lymphocyte cell line, we identified the presence of message for both CC and CXC chemokine receptors. The feline CXCR4 has been shown to facilitate fusion by FIV [44] and we suggest that the feline CCR5 receptor mediates infection of feline cells by M-tropic strains of FIV.
 ...
PMID:Feline peripheral blood mononuclear cells express message for both CXC and CC type chemokine receptors. 1047 Feb 53

Infection and entry of CD4(+) cells by human immunodeficiency virus type 1 (HIV-1) requires a coreceptor molecule, which, in concert with CD4, interacts with the viral envelope glycoprotein (Env), leading to membrane fusion. The principal coreceptors are the CCR5 and CXCR4 chemokine receptors. The suppressive effect of beta-chemokines, principally RANTES, on certain HIV-1 isolates was established before the discovery of the CCR5 receptor, and there have since been multiple reports confirming this initial observation. However, the inhibitory effect of beta-chemokines on HIV-1 infection of macrophages has been controversial. The current study focused on this issue in detail, with a reductionist approach, using assays that measure the effect of beta-chemokines solely on Env-mediated fusion. It is shown that under a variety of culture and differentiation conditions, RANTES maintains a significant and consistent inhibitory effect on CCR5-dependent Env-mediated fusion, and the role of these findings is discussed in relation to the role of beta-chemokines in HIV pathogenesis.
 ...
PMID:Consistent and significant inhibition of human immunodeficiency virus type 1 envelope-mediated membrane fusion by beta-chemokines (RANTES) in primary human macrophages. 1088 83

We examined the role of asparagine-linked glycosylation of the V2 loop of the human immunodeficiency virus (HIV) SF162 envelope on viral replication potential and neutralization susceptibility. We report that the asparagines located at the amino- and carboxy-terminal sites (at positions 154 and 195, respectively), as well as within the V2 loop of the SF162 envelope (at position 186), are glycosylated during in vitro replication of this virus in human peripheral blood mononuclear cells. Our studies indicate that glycosylation of the V2 loop, in particular at its base, facilitates the interaction of the HIV envelope with the CD4 and CCR5 receptor molecules present on the surface of target cells and affects viral replication kinetics in a cell type-dependent manner. In cells expressing high numbers of receptor molecules on their surfaces, the SF162-derived V2 loop-deglycosylated mutant viruses replicate as efficiently as the parental SF162 virus, while in cells expressing small numbers of receptor molecules, the mutant viruses replicate with markedly reduced efficiency. In addition to expanding the viral tropism, V2 loop glycosylation at the three sites examined prevents neutralization by anti-CD4 binding site antibodies. In contrast, glycosylation at the amino- and carboxy-terminal sites of the V2 loop but not within the loop itself offers protection against anti-V3 loop antibodies. Thus, the epitopes masked by the sugar molecules present on the three glycosylation sites examined are not identical but overlap.
 ...
PMID:V2 loop glycosylation of the human immunodeficiency virus type 1 SF162 envelope facilitates interaction of this protein with CD4 and CCR5 receptors and protects the virus from neutralization by anti-V3 loop and anti-CD4 binding site antibodies. 1088 15

The CCR5 beta-chemokine receptor is the coreceptor for macrophage-tropic (M-tropic) strains of HIV-1 and appears to be the principal coreceptor during early stages of human immunodeficiency virus-1 (HIV-1) infection. Approximately 1%-2% of the Western European Caucasian population is homozygous for a 32-bp deletion in the coding region of the CCR5 gene, rendering them less susceptible to HIV infection. These individuals still harbor a normal immune response, thereby making CCR5 an attractive cellular target for anti-HIV therapies. Based on the natural population studies, reduction in CCR5 expression should not affect the physiologic function of the modified cells but should interfere with their susceptibility to HIV-1 infection. To downregulate this receptor, we have designed a hammerhead ribozyme (RZ) that specifically targets the CCR5 mRNA and lacks complementarity to other members of the chemokine receptor gene family. For expression of this highly specific ribozyme, we have taken advantage of the stable transcripts afforded by transcription from the RNA polymerase III (pol III)-based adenoviral VA1 gene. Importantly, the VA1-chimeric ribozyme is stably expressed with a half-life of almost 6 hours. Using this expression system, we show up to 70% downregulation of the elevated levels of CCR5 receptor in the HOS-CD4.CCR5 cell line. The monocytic cell line PM1 was stably transduced with the chimeric VA1 ribozyme constructs. In these cells, substantial resistance to challenge with an M-tropic but not a T-tropic HIV viral strain was observed, demonstrating specificity in downregulating the CCR5 coreceptor. The VA1-CCR5 ribozyme chimeras described in this study should prove useful in both studies of CCR5 receptor function and therapeutic intervention of monocytotropic HIV-1 infection. The VA1 vector described in this study is well suited for the stable cytoplasmic expression of other ribozyme constructs as well.
 ...
PMID:Downregulation of the CCR5 beta-chemokine receptor and inhibition of HIV-1 infection by stable VA1-ribozyme chimeric transcripts. 1098 19

SPC3 is a multibranched peptide containing eight identical GPGRAF motifs which are derived from the human immunodeficiency virus (HIV)-1 gp120 V3 loop consensus sequence. This molecule was reported to prevent the infection of CD4+ cells by various HIV-1 and HIV-2 strains. However, the molecular mode of action of SPC3 remains unclear. Here, we investigated the possibility that SPC3 could interact with alpha/beta-chemokine receptors following observations that, first, the V3 loop is likely to be involved in alpha/beta-chemokine receptor-dependent HIV entry and, second, natural ligands of these receptors are potent inhibitors of cell infection. To address this point, we examined the effects of SPC3 on Xenopus oocytes either uninjected or expressing exogenous human CXCR4 alpha-chemokine receptors. Extracellular applications of micromolar concentrations of SPC3 onto Xenopus oocytes trigger potent inward chloride currents which can be inhibited by increasing extracellular Ca2+ concentration. This effect can be blocked by chloride channel antagonists and is highly specific to SPC3 as it is not triggered by structural analogs of SPC3. The SPC3-induced chloride conductance in oocytes is alpha/beta-chemokine receptor dependent because: (i) SPC3 alters the sensitivity of this channel to external applications of human recombinant MIP-1alpha, a natural ligand of human CCR5 receptor, and (ii) the amplitude of the inward current could be increased by the expression of exogenous human CXCR4 chemokine receptor. The effect of SPC3 appears to rely on the activation of a phospholipase A2 signaling pathway, but is not affected by changes in cytosolic Ca2+ concentration, or by alterations in Gi/Go protein, adenylate cyclase, phospholipase C or protein kinase C activity. Altogether, the data indicate that SPC3 is capable of activating a surface alpha/beta-chemokine-like receptor-mediated signaling pathway in competent cells, thereby triggering, either directly or indirectly, a Ca2+-inactivated chloride conductance.
 ...
PMID:Ion channel activation by SPC3, a peptide derived from the HIV-1 gp120 V3 loop. 1115 2


1 2 3 4 Next >>