Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

It has been proposed that changes in cell surface concentrations of coreceptors may control infections by human immunodeficiency virus type 1 (HIV-1), but the mechanisms of coreceptor function and the concentration dependencies of their activities are unknown. To study these issues and to generate stable clones of adherent cells able to efficiently titer diverse isolates of HIV-1, we generated two panels of HeLa-CD4/CCR5 cells in which individual clones express either large or small quantities of CD4 and distinct amounts of CCR5. The panels were made by transducing parental HeLa-CD4 cells with the retroviral vector SFF-CCR5. Derivative clones expressed a wide range of CCR5 quantities which were between 7.0 x 10(2) and 1.3 x 10(5) molecules/cell as measured by binding antibodies specific for CCR5 and the chemokine [125I]MIP1beta. CCR5 was mobile in the membranes, as indicated by antibody-induced patching. In cells with a large amount of CD4, an unexpectedly low trace of CCR5 (between 7 x 10(2) and 2.0 x 10(3) molecules/cell) was sufficient for maximal susceptibility to all tested HIV-1, including primary patient macrophagetropic and T-cell-tropic isolates. Indeed, the titers as indicated by immunoperoxidase staining of infected foci were as high as the tissue culture infectious doses measured in human peripheral blood mononuclear cells. In contrast, cells with a small amount of CD4 required a much larger quantity of CCR5 for maximal infection by macrophagetropic HIV-1 (ca. 1.0 x 10(4) to 2.0 x 10(4) molecules/cell). Cells that expressed low and high amounts of CD4 were infected with equal efficiencies when CCR5 concentrations were above threshold levels for maximal infection. Our results suggest that the concentrations of CD4 and CCR5 required for efficient infections by macrophagetropic HIV-1 are interdependent and that the requirements for each are increased when the other component is present in a limiting amount. We conclude that CD4 and CCR5 directly or indirectly interact in a concentration-dependent manner within a pathway that is essential for infection by macrophagetropic HIV-1. In addition, our results suggest that multivalent virus-receptor bonds and diffusion in the membrane contribute to HIV-1 infections.
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PMID:Effects of CCR5 and CD4 cell surface concentrations on infections by macrophagetropic isolates of human immunodeficiency virus type 1. 952 5

RANTES has been found to suppress human immunodeficiency virus type 1 (HIV-1) replication. To further elucidate the role of this chemokine in HIV-1 infection, RANTES levels were analyzed in serum and platelet-free plasma (PFP) in 53 HIV-1-infected patients and 20 controls. RANTES levels were significantly elevated in both serum and PFP in all clinical stages of HIV-1 infection, with the highest levels in CDC groups A and B. In longitudinal testing, the progressors were characterized by a pronounced decline in serum levels over time; the nonprogressors, however, had only a slight reduction or an increase in RANTES levels. During 16 weeks of indinavir therapy, there was an increase in circulating RANTES levels and enhanced release of RANTES from stimulated CD8+ lymphocytes. The decline in RANTES levels along with disease progression is compatible with RANTES having a beneficial role in HIV-1-infected patients. The increase in RANTES levels during protease inhibitor-containing regimens may represent a previously unrecognized immunologic effect of such therapy.
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PMID:Circulating levels of RANTES in human immunodeficiency virus type 1 infection: effect of potent antiretroviral therapy. 953 90

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

Like human immunodeficiency virus type 1 (HIV-1) and simian immunodeficiency virus (SIV), HIV-2 requires a coreceptor in addition to CD4 for entry into cells. HIV and SIV coreceptor molecules belong to a family of seven-transmembrane-domain G-protein-coupled receptors. Here we show that primary HIV-2 isolates can use a broad range of coreceptor molecules, including CCR1, CCR2b, CCR3, CCR4, CCR5, and CXCR4. Despite broad coreceptor use, the chemokine ligand SDF-1 substantially blocked HIV-2 infectivity of peripheral blood mononuclear cells, indicating that its receptor, CXCR4, was the predominant coreceptor for infection of these cells. However, expression of CXCR4 together with CD4 on some cell types did not confer susceptibility to infection by all CXCR4-using virus isolates. These data therefore indicate that another factor(s) influences the ability of HIV-2 to replicate in human cell types that express the appropriate receptors for virus entry.
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PMID:A broad range of chemokine receptors are used by primary isolates of human immunodeficiency virus type 2 as coreceptors with CD4. 955 95

The role of human immunodeficiency virus (HIV) strain variability remains a key unanswered question in HIV dementia, a condition affecting around 20% of infected individuals. Several groups have shown that viruses within the central nervous system (CNS) of infected patients constitute an independently evolving subset of HIV strains. A potential explanation for the replication and sequestration of viruses within the CNS is the preferential use of certain chemokine receptors present in microglia. To determine the role of specific chemokine coreceptors in infection of adult microglial cells, we obtained a small panel of HIV type 1 brain isolates, as well as other HIV strains that replicate well in cultured microglial cells. These viruses and molecular clones of their envelopes were used in infections, in cell-to-cell fusion assays, and in the construction of pseudotypes. The results demonstrate the predominant use of CCR5, at least among the major coreceptors, with minor use of CCR3 and CXCR4 by some of the isolates or their envelope clones.
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PMID:Chemokine receptor utilization by human immunodeficiency virus type 1 isolates that replicate in microglia. 955 14

The CCR5-Delta32 deletion obliterates the CCR5 chemokine and the human immunodeficiency virus (HIV)-1 coreceptor on lymphoid cells, leading to strong resistance against HIV-1 infection and AIDS. A genotype survey of 4,166 individuals revealed a cline of CCR5-Delta32 allele frequencies of 0%-14% across Eurasia, whereas the variant is absent among native African, American Indian, and East Asian ethnic groups. Haplotype analysis of 192 Caucasian chromosomes revealed strong linkage disequilibrium between CCR5 and two microsatellite loci. By use of coalescence theory to interpret modern haplotype genealogy, we estimate the origin of the CCR5-Delta32-containing ancestral haplotype to be approximately 700 years ago, with an estimated range of 275-1,875 years. The geographic cline of CCR5-Delta32 frequencies and its recent emergence are consistent with a historic strong selective event (e.g. , an epidemic of a pathogen that, like HIV-1, utilizes CCR5), driving its frequency upward in ancestral Caucasian populations.
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PMID:Dating the origin of the CCR5-Delta32 AIDS-resistance allele by the coalescence of haplotypes. 958 95

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

We examined the effect of immune stimulation by a human immunodeficiency virus type 1 (HIV-1) immunogen (Remune) compared to a non-HIV vaccine (influenza) on HIV-1-specific immune responses in HIV-1-seropositive subjects. HIV-1 p24 antigen-stimulated lymphocyte proliferation was not augmented after immunization with the influenza vaccine. In contrast, subjects increased their lymphocyte proliferative responses to p24 antigen after one immunization with HIV-1 immunogen (Remune) (gp120-depleted inactivated HIV-1 in incomplete Freund's adjuvant). Furthermore, p24 antigen-stimulated beta-chemokine production (RANTES, MIP-1alpha, MIP-1beta) was also augmented after immunization with the HIV-1 immunogen but not influenza vaccine. Taken together, these results suggest that in this cohort, HIV-specific immune responses to p24 antigen can be augmented after immunization with an HIV-1 immunogen. The ability to upregulate immune responses to the more conserved core proteins may have important implications in the development of immunotherapeutic interventions for HIV-1 infection.
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PMID:In vitro p24 antigen-stimulated lymphocyte proliferation and beta-chemokine production in human immunodeficiency virus type 1 (HIV-1)-seropositive subjects after immunization with an inactivated gp120-depleted HIV-1 immunogen (Remune). 960 82


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