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)

Chemokines have been implicated as protective factors against human immunodeficiency virus (HIV) infection, competing for binding to receptors that also function as coreceptors for HIV. In this study of HIV-positive donors, peripheral blood mononuclear cell (PBMC) culture resistance to endogenous and exogenous HIV correlated with low plasma viremia and high in vitro RANTES production. However, resistant cells were not rendered susceptible by neutralization of C-C chemokines, and addition of C-C chemokines did not consistently suppress endogenous virus or exogenous HIV-1MN. In contrast, CD8 T cell depletion markedly decreased the frequency of resistant cultures without reducing C-C chemokine production. Among newly infected persons, half exhibited phenotype switching from preinfection susceptibility to postinfection resistance, suggesting that genetically predetermined constitutive cytokine production or allelic receptor expression are not generally responsible for in vitro resistance and nonprogression.
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PMID:Chemokine-independent in vitro resistance to human immunodeficiency virus (HIV-1) correlating with low viremia in long-term and recently infected HIV-1-positive persons. 935 15

Human CC chemokine receptor 5 (CCR5), mediates the activation of cells by the chemokines macrophage inflammatory protein-1alpha, macrophage inflammatory protein-1beta, and RANTES, and serves as a fusion cofactor for macrophage-tropic strains of human immunodeficiency virus type 1. To understand the molecular mechanisms that regulate human CCR5 gene expression, we initiated studies to determine its genomic and mRNA organization. Previous studies have identified a single CCR5 mRNA isoform whose open reading frame is intronless. We now report the following novel findings. 1) Complex alternative splicing and multiple transcription start sites give rise to several distinct CCR5 transcripts that differ in their 5'-untranslated regions (UTR). 2) The gene is organized into four exons and two introns. Exons 2 and 3 are not interrupted by an intron. Exon 4 and portions of exon 3 are shared by all isoforms. Exon 4 contains the open reading frame, 11 nucleotides of the 5'-UTR and the complete 3'-UTR. 3) The transcripts appear to be initiated from two distinct promoters: an upstream promoter (PU), upstream of exon 1, and a downstream promoter (PD), that includes the "intronic" region between exons 1 and 3. 4) PU and PD lacked the canonical TATA or CAAT motifs, and are AT-rich. 5) PD demonstrated strong constitutive promoter activity, whereas PU was a weak promoter in all three leukocyte cell environments tested (THP-1, Jurkat, and K562). 6) We provide evidence for polymorphisms in the noncoding sequences, including the regulatory regions and 5'-UTRs. The structure of CCR5 was strikingly reminiscent of the overall structure of other chemokine/chemoattractant receptors, underscoring an important evolutionarily conserved function for a prototypical gene structure. This is the first description of functional promoters for any CC chemokine receptor gene, and we speculate that the complex pattern of splicing events and dual promoter usage may function as a versatile mechanism to create diversity and flexibility in the regulation of CCR5 expression.
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PMID:The human CC chemokine receptor 5 (CCR5) gene. Multiple transcripts with 5'-end heterogeneity, dual promoter usage, and evidence for polymorphisms within the regulatory regions and noncoding exons. 938 1

To investigate the role played by chemokines in the natural history of human immunodeficiency virus (HIV) infection, we measured the plasma levels of RANTES. MIP-1 alpha and MIP-1 beta in a cohort of patients with primary HIV-1 infection (PHI) followed longitudinally. The cohort included 17 patients with well-documented history of acute HIV syndrome within two months of the first observation. The mean plasma concentration of RANTES, but not that of MIP-1 alpha or MIP-1 beta, was significantly higher in patients with PHI (192.3 ng/ml) than in five HIV-seronegative controls (8.0 ng/ml) studied during the same time period. Treatment of blood with a cocktail of drugs preventing platelet activation, followed by high-speed centrifugation, reduced the levels of RANTES by approximately 2 logs both in patients and in controls, indicating that the bulk of RANTES was released by platelets, which are known to store this chemokine in their alpha-granules, in the immediate aftermath of blood drawing. No correlation was seen between the levels of RANTES and the number of HIV genome equivalents in plasma. These data suggest that large amounts of pre-formed RANTES are stored in platelets and, possibly, in other blood cells during the early phases of HIV infection. The possible role of this HIV-suppressive chemokine in the control of viral replication during PHI remains to be established.
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PMID:Increased plasma levels of the C-C chemokine RANTES in patients with primary HIV-1 infection. 941 60

We have constructed transgenic (Tg) mice expressing the entire human immunodeficiency virus type 1 (HIV-1) coding sequences in cells targeted by HIV-1 infection in humans. These Tg mice developed a severe AIDS-like disease leading to early death (< 1 month). They developed muscle wasting, severe atrophy and fibrosis of lymphoid organs, tubulointerstitial nephritis, and lymphoid interstitial pneumonitis. In addition the expression of RANTES was increased in various tissues of these Tg mice relative to that in the normal controls. Disease appearance was correlated with the levels of transgene expression. The numerous pathologies observed in these mice are remarkably similar to those observed in human AIDS and, more specifically, in pediatric AIDS.
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PMID:Transgenic mice expressing human immunodeficiency virus type 1 in immune cells develop a severe AIDS-like disease. 942 Feb 7

We have studied the breadth and potency of the inhibitory actions of the CC chemokines macrophage inhibitory protein 1alpha (MIP-1alpha), MIP-1beta, and RANTES against macrophage-tropic (M-tropic) primary isolates of human immunodeficiency virus type 1 (HIV-1) and of the CXC chemokine stromal cell-derived factor 1alpha against T-cell-tropic (T-tropic) isolates, using mitogen-stimulated primary CD4+ T cells as targets. There was considerable interisolate variation in the sensitivity of HIV-1 to chemokine inhibition, which was especially pronounced for the CC chemokines and M-tropic strains. However, this variation was not obviously dependent on the genetic subtype (A through F) of the virus isolates. Peripheral blood mononuclear cell donor-dependent variation in chemokine inhibition potency was also observed. Among the CC chemokines, the rank order for potency (from most to least potent) was RANTES, MIP-1beta, MIP-1alpha. Some M-tropic isolates, unexpectedly, were much more sensitive to RANTES than to MIP-1beta, whereas other isolates showed sensitivities comparable to those of these two chemokines. Down-regulation of the CCR5 and CXCR4 receptors occurred in cells treated with the cognate chemokines and probably contributes to anti-HIV-1 activity. Thus, for CCR5, the rank order for down-regulation was also RANTES, MIP-1beta, MIP-1alpha.
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PMID:Genetic subtype-independent inhibition of human immunodeficiency virus type 1 replication by CC and CXC chemokines. 942 Feb 38

Recent studies have demonstrated that the beta-chemokines RANTES, MIP-1alpha, and MIP-1beta suppress human immunodeficiency virus type 1 (HIV-1) replication in vitro and may play an important role in protecting exposed but uninfected individuals from HIV-1 infection. However, levels of beta-chemokines in AIDS patients are comparable to and can exceed levels in nonprogressing individuals, indicating that global beta-chemokine production may have little effect on HIV-1 disease progression. We sought to clarify the role of beta-chemokines in nonprogressors and AIDS patients by examination of beta-chemokine production and HIV-1 infection in patient T-lymphocyte clones established by herpesvirus saimiri immortalization. Both CD4+ and CD8+ clones were established, and they resembled primary T cells in their phenotypes and expression of activated T-cell markers. CD4+ T-cell clones from all patients had normal levels of mRNA-encoding CCR5, a coreceptor for non-syncytium-inducing (NSI) HIV-1. CD4+ clones from nonprogressors and CD8+ clones from AIDS patients secreted high levels of RANTES, MIP1alpha, and MIP-1beta. In contrast, CD4+ clones from AIDS patients produced no RANTES and little or no MIP-1alpha or MIP-1beta. The infection of CD4+ clones with the NSI HIV-1 strain ADA revealed an inverse correlation to beta-chemokine production; clones from nonprogressors were poorly susceptible to ADA replication, but clones from AIDS patients were highly infectable. The resistance to ADA infection in CD4+ clones from nonprogressors could be partially reversed by treatment with anti-beta-chemokine antibodies. These results indicate that CD4+ cells can be protected against NSI-HIV-1 infection in culture through endogenously produced factors, including beta-chemokines, and that beta-chemokine production by CD4+, but not CD8+, T cells may constitute one mechanism of disease-free survival for HIV-1-infected individuals.
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PMID:Endogenous production of beta-chemokines by CD4+, but not CD8+, T-cell clones correlates with the clinical state of human immunodeficiency virus type 1 (HIV-1)-infected individuals and may be responsible for blocking infection with non-syncytium-inducing HIV-1 in vitro. 942 Mar 4

Five peptides corresponding to the amino-terminal sequence of RANTES (regulated upon activation, normal T-cell expressed and secreted), which is known to be the critical region for chemotaxis, were synthesized, and their anti-human immunodeficiency virus (HIV)-1 activity was examined to obtain a lead compound useful for the development of chemokine receptor-directed anti-HIV-1 drugs. A decapeptide corresponding to positions 1-10 [Ac-(10Ala-RANTES 1-10)-NH2] showed significant anti-HIV-1 activity. Ac-(10Ala, 11Ala-RANTES 5-14)-NH2 was also active, but less potent than the former. Other peptides corresponding to the positions 6-14, 7-14, and 8-14 did not show anti-HIV-1 activity. These results indicate that the sequence 1-10 of RANTES is important for the anti-HIV-1 effect.
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PMID:Synthesis of some peptides corresponding to the active region of RANTES for chemotaxis and evaluation of their anti-human immunodeficiency virus-1 activity. 943 85

Macrophage inflammatory protein (MIP)-1alpha, MIP-1beta, and RANTES production were measured by ELISA in whole blood that had been stimulated for 4.5 h with phytohemagglutinin. The blood was from 90 healthy human immunodeficiency virus (HIV)-negative controls and from 245 HIV-infected subjects who were followed for < or = 4.5 years. HIV-infected persons without AIDS had increased levels of MIP-1alpha, MIP-1beta, and RANTES (P < .01) compared with levels in controls. Subjects with AIDS, compared with controls, had decreased production levels of MIP-1beta (P < .0001) and similar levels of MIP-1alpha and RANTES. A high level of MIP-1beta production was associated with a decreased risk of progressing to AIDS or death, as determined by univariate analysis (P < .01) and adjusted for CD4 cell count and age (P = .07, P = .06, respectively). The findings suggest that the production level of beta-chemokine changes during HIV infection and that a high level of beta-chemokine production in peripheral blood lymphocytes may be associated with less rapid disease progression in HIV infection.
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PMID:Production of beta-chemokines in human immunodeficiency virus (HIV) infection: evidence that high levels of macrophage inflammatory protein-1beta are associated with a decreased risk of HIV disease progression. 946 18

Human immunodeficiency virus, type I (HIV-1) cell-type tropism is dictated by chemokine receptor usage: T-cell line tropic viruses use CXCR4, whereas monocyte tropic viruses primarily use CCR5 as fusion coreceptors. CC chemokines macrophage inflammatory protein (MIP)-1alpha, MIP-1beta, and RANTES (regulated on activation normal T cell expressed and secreted) inhibit CD4/CCR5-mediated HIV-1 cell fusion. MCP-2 is also a member of the CC chemokine subfamily and has the capacity to interact with at least two receptors including CCR-1 and CCR2B. In an effort to further characterize the binding properties of MCP-2 on leukocytes, we observed that MCP-2, but not MCP-1, effectively competed with MIP-1beta for binding to monocytes, suggesting that MCP-2 may interact with CCR5. As predicted, MCP-2 competitively inhibited MIP-1beta binding to HEK293 cells stably transfected with CCR5 (CCR5/293 cells). MCP-2 also bound to and induced chemotaxis of CCR5/293 cells with a potency comparable with that of MIP-1beta. Confocal microscopy indicates that MCP-2 caused remarkable and dose-dependent internalization of CCR5 in CCR5/293 cells. Furthermore, MCP-2 inhibited the entry/replication of HIV-1ADA in CCR5/293 cells coexpressing CD4. These results indicated that MCP-2 uses CCR5 as one of its functional receptors and is an additional potent natural inhibitor of HIV-1.
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PMID:Monocyte chemotactic protein-2 activates CCR5 and blocks CD4/CCR5-mediated HIV-1 entry/replication. 946 73

CD8+ lymphocytes are believed to be important in host defence against the human immunodeficiency virus (HIV)-1, inhibiting HIV-1 replication through both cytolytic and non-cytolytic pathways. The cytolytic pathway involves calcium-dependent exocytosis of perforin and granzyme proteases, as well as Fas-mediated programmed cell death, whereas the noncytolytic pathway involves the release of chemokines that prevent viral entry. Using granzyme A as a marker of cytolytic granule proteins, and macrophage inflammatory protein (MIP)-1alpha and RANTES as markers of HIV-1 inhibitory chemokines, we show that these two very different mediators of viral inhibition are both localized in the cytolytic granules of HIV-1-specific CD8+ cytotoxic T lymphocytes (CTL). Following antigen-specific activation, these mediators are secreted together, facilitating both lysis of virion-producing cells and the inhibition of free virus. In addition, RANTES, MIP-1alpha and MIP-1beta are secreted by CTL as a macromolecular complex containing sulphated proteoglycans. This association appears to have a functional significance, because heparan sulphate facilitates RANTES inhibition of HIV-1 infection of monocytes.
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PMID:Beta-chemokines are released from HIV-1-specific cytolytic T-cell granules complexed to proteoglycans. 949 45


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