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)

CXCR4 is both a chemokine receptor and entry co-receptor for T-cell line-adapted human immunodeficiency virus type 1. The genomic organization and promoter function for the entire transcription unit of CXCR4 were determined. The gene contains 2 exons of 103 and 1563 base pairs (bp) interrupted by a 2132-bp intron precisely between codons 5 and 6 of the coding sequences. A transcription start site was identified 88 bp upstream of the initiation codon, and a polyadenylate addition site was identified 22 bp 3' to a polyadenylation signal. Transient expression assays defined a minimal promoter at positions -114 to +43 relative to the transcription start site. This region contains a TATA box, a nuclear respiratory factor-1 (NRF-1) site, and two GC boxes. Specific factor binding to the NRF-1 site and GC boxes were demonstrated by gel mobility shifts and DNase I footprinting. Site-directed mutagenesis showed that the NRF-1 site is crucial for promoter activity providing the first evidence for the regulation of a signal transduction gene by NRF-1. Sequences between -691 and -191 repress CXCR4 promoter activity. Further study of these regulatory elements will be important to understanding how CXCR4 functions as both a chemokine receptor and human immunodeficiency virus type 1 entry co-receptor.
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PMID:Genomic organization and functional characterization of the chemokine receptor CXCR4, a major entry co-receptor for human immunodeficiency virus type 1. 946 39

Infection of CD4-positive cells by human immunodeficiency virus type 1 (HIV-1) requires functional interaction of the viral envelope protein with a coreceptor belonging to the chemokine receptor family of seven-membrane-spanning receptors. For the majority of macrophage-tropic HIV-1 isolates, the physiologically relevant coreceptor is the human CCR-5 (hCCR-5) receptor. Although the murine homolog of CCR-5 (mCCR-5) is unable to mediate HIV-1 infection, chimeric hCCR-5/mCCR-5 molecules containing single extracellular domains derived from hCCR-5 are effective coreceptors for certain macrophage-tropic HIV-1 isolates. Here, we have sought to identify residues in hCCR-5 critical for HIV-1 infection by substitution of mCCR-5-derived residues into the context of functional chimeric hCCR-5/mCCR-5 receptor molecules. Using this strategy, we demonstrate that residues 7, 13, and 15 in the first extracellular domain and residue 180 in the third extracellular domain of CCR-5 are important for HIV-1 envelope-mediated membrane fusion. Of interest, certain substitutions, for example, at residues 184 and 185 in the third extracellular domain, have no phenotype when introduced individually but strongly inhibit hCCR-5 coreceptor function when present together. We hypothesize that these changes, which do not preclude chemokine receptor function, may inhibit a conformational transition in hCCR-5 that contributes to HIV-1 infection. Finally, we report that substitution of glycine for valine at residue 5 in CCR-5 can significantly enhance the level of envelope-dependent cell fusion by expressing cells. The diversity of the mutant phenotypes observed in this mutational analysis, combined with their wide distribution across the extracellular regions of CCR-5, emphasizes the complexity of the interaction between HIV-1 envelope and coreceptor.
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PMID:Multiple residues contribute to the inability of murine CCR-5 to function as a coreceptor for macrophage-tropic human immunodeficiency virus type 1 isolates. 949 44

More than a decade after the first description of HIV DNA in the nervous system the pathophysiology of HIVD remains largely enigmatic, with data supporting a number of potential mechanisms for the development of neuronal dysfunction. Nevertheless, a few key findings have considerable support in the literature devoted to this subject: 1. HIV dementia is caused by HIV itself; no other pathogen has been consistently found in the brains of patients with HIVD. 2. In comparison with other viral encephalopathies, there appears to be a significant discordance between the amount of virus being produced in the brains of patients with HIVD and the degree of neurological deterioration. 3. The key cell types responsible for viral production within the CNS are the resident macrophages or microglial cells. 4. Other elements within the CNS, particularly astrocytes, are probably infected with HIV as well, but all of these infections are highly restricted in terms of production of virus or viral structural proteins. 5. At least one component of the pathogenesis of HIVD may be the generation of neurotoxins by infected microglia, although the type of neurotoxin, and the specific compound most likely to be involved, are quite controversial. Advances with combination antiviral therapy have successfully reduced plasma viral load in a high proportion of individuals, leading to the speculation (previously almost heretical) that it may be possible to eradicate HIV completely from the systemic immune system. If that were the case, potential "sanctuary" sites such as the immunologically protected CNS might remain as important reservoirs for reseeding of lymphoid tissues. Microglia may be particularly suited for this purpose because they are long lived, can produce HIV for several weeks (at least in culture), and they are apparently relatively immune to virus-induced cytopathology such as syncytium formation. One can speculate about several scenarios resulting from the continued presence of replication-competent HIV within brain. In the worst case, a smoldering infection of the nervous system could lead to neurological deterioration without reinfection of systemic immune cells. The epidemiological data indicating that HIVD is a disease primarily associated with immunodeficiency suggest that the systemic immune system plays a role in maintaining virus residing within the CNS under control. Thus it is quite possible that this scenario would not occur for many years after the systemic infection is controlled. Alternatively, virus could be transported from the CNS by circulating lymphocytes and monocytes and reinfect systemic organs. This would necessitate restarting therapy for those individuals who were previously thought to be cured, but presumably virus within the CNS would not have developed resistance to antivirals. In either case, the techniques currently available do not permit an accurate assessment of CNS HIV load in living people, and this question will remain unanswered until antivirals are discontinued in a few individuals with persistently negative tests for systemic virus. In addition to this most critical question, the relationship between viral levels and HIVD is largely unexplored, as is the possibility that some strains are particularly virulent or neuroinvasive. Furthermore, the potential contribution of host genotype in the development of dementia is unknown. In view of the strong influence of major chemokine receptor (CCR5) truncations on HIV replication, it is entirely possible that more discrete genetic polymorphisms have a subtle effect on either brain invasion or virulence.
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PMID:The effects of human immunodeficiency virus in the central nervous system. 952 Sep 95

Infection by human immunodeficiency virus (HIV) requires the presence of a chemokine receptor on the susceptible cell. The expression of two different chemokine receptors on macrophages and lymphocytes explains the selectivity of different HIV isolates. The rationale behind the choice of the chemokine receptor (CCR5) expressed on macrophages as a therapeutic target is based on the epidemiological studies of the impact on HIV infectivity of a human mutation that prevents expression of this receptor. CCR5 is a member of the G-protein-coupled receptor family, which has yet to be characterized structurally at atomic resolution. Efforts to model the three-dimensional structure of such receptors and to characterize them experimentally are underway in many laboratories. As an example, structural studies determining the bound conformation of the C-terminal peptide of the alpha-subunit of transducin, the relevant G-protein of vision, with rhodopsin are presented.
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PMID:Therapeutic approaches to human immunodeficiency virus: structural studies on G-protein-coupled receptors. 953 75

Cellular infection by the human immunodeficiency virus type 1 (HIV-1) requires interaction of the viral envelope protein with CD4 and at least one additional cell surface molecule, termed a "cofactor" or "coreceptor." Recent discoveries have determined that macrophage-tropic strains of HIV-1 which are largely responsible for sexual transmission require the beta-chemokine receptor CCR5 in addition to CD4, while the T cell tropic viruses that emerge later after infection use the alpha-chemokine receptor CXCR4. Thus, both CD4 and the appropriate chemokine receptor must be expressed on the cell surface in order for HIV-1 to enter the cell and establish an infection. The in vivo importance of CCR5 for HIV-1 is demonstrated by the finding that individuals homozygous for a 32 bp deletion (delta 32) in the CCR5 gene that renders them effectively CCR5-negative are highly resistant to virus infection. In this review, the structure-function correlates of the chemokine receptors that serve as major coreceptors for HIV-1 and simian immunodeficiency virus entry will be reviewed. Since certain chemokines have been implicated as stem cell inhibitory factors, the biological consequences of chemokine receptor expression as it relates to HIV-1-associated hematodyspoiesis will also be discussed.
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PMID:An intricate Web: chemokine receptors, HIV-1 and hematopoiesis. 955 31

Studies on the development and function of CD4+ TH1 and TH2 cells during the progression to AIDS may increase the understanding of AIDS pathogenesis. The preferential replication of human immunodeficiency virus (HIV) in either TH1 or TH2 cells could alter the delicate balance of the immune response. TH1 (gamma interferon [IFN-gamma] positive, interleukin-4 [IL-4] and IL-5 negative) and TH2 (IFN-gamma negative, IL-4 and IL-5 positive) clones, developed from several healthy donors, pedigreed by reverse transcriptase PCR (RT-PCR) and enzyme linked immunosorbent assay have similar levels of cell surface expression of CD4 and several chemokine receptor cofactors necessary for viral entry. After activation by specific antigens and infection with T-cell-tropic strains of HIV type 1 (HIV-1), TH1 and TH2 clones showed similar levels of viral entry and reverse transcription. At days 3 through 14 postinfection, HIV replicated to similar levels in several TH1 and TH2 clones as measured by release of HIV p24 and total number of copies of gag RNA/total cell RNA as measured by RT-PCR. When values were normalized for viable cell number in three clones of each type, there was up to twofold more HIV RNA in TH1 than TH2 cells. In addition, several primary monocytotropic HIV-1 strains were able to replicate to similar levels in TH1 and TH2 cells. These studies suggest that the importance of TH1 and TH2 subsets in AIDS pathogenesis transcends clonal differences in their ability to support HIV replication.
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PMID:Similar levels of human immunodeficiency virus type 1 replication in human TH1 and TH2 clones. 957 96

Human immunodeficiency virus (HIV) envelope binds CD4 and a chemokine receptor in sequence, releasing hydrophobic viral gp41 residues into the target membrane. HIV entry required actin-dependent concentration of coreceptors, which could be disrupted by cytochalasin D (CytoD) without an effect on cell viability or mitosis. Pretreatment of peripheral blood mononuclear cells, but not virus, inhibited entry and infection. Immunofluorescent confocal microscopy of activated cells revealed CD4 and CXCR4 in nonoverlapping patterns. Addition of gp120 caused polarized cocapping of both molecules with subsequent pseudopod formation, while CytoD pretreatment blocked these membrane changes completely.
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PMID:Actin-dependent receptor colocalization required for human immunodeficiency virus entry into host cells. 957 99

CXCR4, a seven transmembrane domain G-protein-coupled receptor for the Cys-X-Cys class of chemokines, is one of several chemokine receptors that can act as a co-receptor with CD4 for the human immunodeficiency virus (HIV-1) glycoprotein gp120 [1-3]. CXCR4 can mediate the entry of HIV-1 strains that specifically infect T cells, such as the IIB strain (see [4] for review). Recent reports indicate that gp120 can signal through CXCR4 [5] and it has been suggested that signal transduction, mediated by the viral envelope, might influence viral-associated cytopathicity or apoptosis [6]. Neuronal apoptosis is a feature of HIV-1 infection in the brain [7,8], although the exact mechanism is unknown. Here, we address the possible role of CXCR4 in inducing apoptosis using cells of the hNT human neuronal cell line; these cells resemble immature post-mitotic cholinergic neurons and have a number of neuronal characteristics [9-15]. We have previously shown that gp120 from the HIV-1 IIIB strain binds with high affinity to CXCR4 expressed on hNT neurons [15]. We now find that both IIIB gp120 and the Cys-X-Cys chemokine SDF-1 alpha can directly induce apoptosis in hNT neurons in the absence of CD4 and in a dose-dependent manner. To our knowledge, this is the first report of a chemokine and an HIV-1 envelope glycoprotein eliciting apoptotic responses through a chemokine receptor.
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PMID:Neuronal apoptosis induced by HIV-1 gp120 and the chemokine SDF-1 alpha is mediated by the chemokine receptor CXCR4. 960 45

Leukocyte chemoattractants act through a rapidly growing subfamily of G protein-coupled receptors. We report the cloning of a novel human gene encoding an orphan receptor (ChemR23) related to the C3a, C5a and formyl Met-Leu-Phe receptors, and more distantly to the subfamilies of chemokine receptors. ChemR23 transcripts were found to be abundant in monocyte-derived dendritic cells and macrophages, treated or not with LPS. Low expression could also be detected by reverse transcription-PCR in CD4+ T lymphocytes. The gene encoding ChemR23 was assigned by radiation hybrid mapping to the q21.2-21.3 region of human chromosome 12, outside the gene clusters identified so far for chemoattractant receptors. Given the increasing number of chemoattractant receptors used by HIV-1, HIV-2 and SIV as coreceptors, ChemR23 was tested in fusion assays for potential coreceptor activity by a range of viral strains. None of the tested HIV-2 strains made use of ChemR23 as a coreceptor, but several SIV strains (SIVmac316, SIVmac239, SIVmacl7E-Fr and SIVsm62A), as well as a primary HIV-1 strain (92UG024-2) used it efficiently. ChemR23 therefore appears as a coreceptor for immunodeficiency viruses that does not belong to the chemokine receptor family. It is also a putative chemoattractant receptor relatively specific for antigen-presenting cells, and it could play an important role in the recruitment or trafficking of these cell populations. Future work will be required to identify the ligand(s) of this new G protein-coupled receptor and to define its precise role in the physiology of dendritic cells and macrophages.
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PMID:ChemR23, a putative chemoattractant receptor, is expressed in monocyte-derived dendritic cells and macrophages and is a coreceptor for SIV and some primary HIV-1 strains. 960 76

Chemokine receptors (CR), which can mediate migration of immune cells to the site of inflammation, also function as coreceptors for human immunodeficiency virus (HIV) entry into CD4+ T lymphocytes and antigen-presenting cells. We demonstrate here that interferon-gamma (IFN-gamma) increases the expression of chemokine receptors CCR1, CCR3, and CCR5 in monocytoid U937 cells as detected by cell surface molecule labeling and mRNA expression, as well as by intracellular calcium mobilization and cell migration in response to specific ligands. The increased expression of these chemokine receptors also results in an enhanced HIV-1 entry into cells. Our data provide evidence for a relationship of cellular pathways that are induced by IFN-gamma with those that regulate chemokine receptor expression.
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PMID:Interferon-gamma increases expression of chemokine receptors CCR1, CCR3, and CCR5, but not CXCR4 in monocytoid U937 cells. 961 37


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