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)

C-C chemokine receptor 5 (CCR5) is the primary coreceptor for human immunodeficiency virus type 1 (HIV-1) infection. Native chemokines that bind to CCR5 inhibit HIV-1 infection, albeit weakly, but chemically modified chemokines inhibit infection more efficiently. We have investigated the inhibitory mechanism of three N-terminally modified RANTES variants (AOP-, NNY-, and PSC-RANTES) with the MT-2 human T-cell line stably expressing either native or mutated CCR5. The RANTES analogues showed the same rank order (PSC > NNY > AOP) in their capacity to induce prolonged CCR5 internalization, inhibit surface reexpression, and prevent HIV-1 infection on MT-2 cells expressing wild-type CCR5 or CCR5 with four C-terminal serine phosphorylation sites mutated to alanine. None of the RANTES analogues caused internalization of a C-terminal cytoplasmic domain deletion mutant of CCR5, and each derivative had equal potency in inhibiting HIV-1 infection of MT-2 cells expressing this mutant. We conclude that the C-terminal cytoplasmic residues of CCR5 are necessary for receptor sequestration by RANTES analogues but that the process and the relative activity of each derivative are not dependent upon phosphorylation of the C-terminal serine residues. Two mechanisms of antiviral activity are demonstrated: receptor blockade and receptor sequestration. Potency correlates with the ability to induce CCR5 sequestration but not with receptor binding, suggesting that sequestration may make the greater contribution to antiviral activity.
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PMID:Two mechanisms for human immunodeficiency virus type 1 inhibition by N-terminal modifications of RANTES. 1254 51

There is a relationship between CD4-T-cell number and circulating interleukin 7 (IL-7) levels in human immunodeficiency virus (HIV)-positive individuals. Here, we show that IL-7 induced a dose-dependent production of CCL3 (MIP-1alpha), CCL4 (MIP-1beta), and CCL5 (RANTES) in peripheral blood mononuclear cells (PBMC), ex vivo tonsil lymphoid tissue of HIV(-) individuals, and PBMC from HIV(+) individuals, suggesting that IL-7 may regulate beta-chemokine production in vivo. In a cross-sectional study of HIV(+) individuals (n = 130), a weak but significant correlation between IL-7 and RANTES was noted (r = 0.379; P < 0.001). Remarkably, the correlation between IL-7 and RANTES increased to an r value of 0.798 (P < 0.001) if individuals with low CD4 cell counts (<200 cells/ micro l) were excluded from the analysis. Our results suggest that there is a relationship between IL-7 and the production of RANTES both in vitro and in vivo that is lost in immune-compromised patients (CD4 count of <200 cells/ micro l) but that could be restored by antiretroviral therapy. Unlike the case for IL-7, high levels of RANTES suggest an intermediate stage of HIV disease progression.
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PMID:Interleukin-7-dependent production of RANTES that correlates with human immunodeficiency virus disease progression. 1263 95

Acquired immunodeficiency syndrome (AIDS)-associated dementia is often characterized by chronic inflammation, with infected macrophage infiltration of the CNS resulting in the production of human immunodeficiency virus type 1 (HIV-1) products, including tat, and neurotoxins that contribute to neuronal loss. In addition to their established role in leukocyte recruitment and activation, we identified an additional role for chemokines in the CNS. Monocyte chemoattractant protein-1 (MCP-1 or CCL2) and regulated upon activation normal T cell expressed and secreted (RANTES) were found to protect mixed cultures of human neurons and astrocytes from tat or NMDA-induced apoptosis. Neuronal and astrocytic apoptosis in these cultures was significantly inhibited by co-treatment with MCP-1 or RANTES but not IP-10. The protective effect of RANTES was blocked by antibodies to MCP-1, indicating that RANTES protection is mediated by the induction of MCP-1. The NMDA blocker, MK801, also abolished the toxic effects of both tat and NMDA. Tat or NMDA treatment of mixed cultures for 24 h resulted in increased extracellular glutamate ([Glu]e) and NMDA receptor 1 (NMDAR1) expression, potential contributors to apoptosis. Co-treatment with MCP-1 inhibited tat and NMDA-induced increases in [Glu]e and NMDAR1, and also reduced the levels and number of neurons containing intracellular tat. These data indicate that MCP-1 may play a novel role as a protective agent against the toxic effects of glutamate and tat.
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PMID:MCP-1 (CCL2) protects human neurons and astrocytes from NMDA or HIV-tat-induced apoptosis. 1275 88

The chemokine receptors CCR5 and CXCR4 are promising non-virus-encoded targets for human immunodeficiency virus (HIV) therapy. We describe a selection procedure to isolate mutant forms of RANTES (CCL5) with antiviral activity considerably in excess of that of the native chemokine. The phage-displayed library of randomly mutated and N-terminally extended variants was screened by using live CCR5-expressing cells, and two of the selected mutants, P1 and P2, were further characterized. Both were significantly more potent HIV inhibitors than RANTES, with P2 being the most active (50% inhibitory concentration of 600 pM in a viral coat-mediated cell fusion assay, complete protection of target cells against primary HIV type 1 strains at a concentration of 10 nM). P2 resembles AOP-RANTES in that it is a superagonist of CCR5 and potently induces receptor sequestration. P1, while less potent than P2, has the advantage of significantly reduced signaling activity via CCR5 (30% of that of RANTES). Additionally, both P1 and P2 exhibit not only significantly increased affinity for CCR5 but also enhanced receptor selectivity, retaining only trace levels of signaling activity via CCR1 and CCR3. The phage chemokine approach that was successfully applied here could be adapted to other chemokine-chemokine receptor systems and used to further improve the first-generation mutants reported in this paper.
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PMID:Human immunodeficiency virus type 1 entry inhibitors selected on living cells from a library of phage chemokines. 1276 83

Acyclic nucleoside phosphonates are novel class of virostatics effective against replication of both DNA-viruses and retroviruses. We found recently, that in addition to the antimetabolic mode of action, some acyclic nucleoside phosphonates such as 9-[2-(phosphonomethoxy)propyl]adenine [(R)-PMPA; tenofovir], which is used in treatment of human immunodeficiency virus (HIV) infection, possess immunostimulatory and immunomodulatory activities known to interfere with replication of viruses. The present experiments analyzed immunobiological effects of more than 70 novel derivatives of acyclic nucleoside phosphonates. They comprise substitutions at the N6-amino function of adenine (A) or 2,6-diaminopurine (DAP) by monoalkyl, dialkyl, cycloalkyl, alkenyl, alkynyl or substituted alkyl group, and at the N9-side chain represented by (R)- or (S)-enantiomeric 9-[2-(phosphonomethoxy)ethyl] (PME) and 9-[2-(phosphonomethoxy)propyl] (PMP) moieties. Their biological effects were investigated in vitro using mouse resident peritoneal macrophages. A number of the compounds under scrutiny, mainly the N6-cycloalkyl derivatives of 9-[2-(phosphonomethoxy)ethyl]2,6-diaminopurine (PMEDAP) and (R)-enantiomeric 9-[2-(phosphonomethoxy)propyl]adenine [(R)-PMPDAP] stimulate secretion of cytokines [tumor necrosis factor-alpha (TNF-alpha), interleukin-10 (IL-10)] and chemokines ["regulated-upon-activation, normal T expressed and secreted" (RANTES), macrophage inflammatory protein-1alpha (MIP-1alpha)]. Moreover, they substantially augment production of nitric oxide (NO) triggered by interferon-gamma. The effects are produced in a dose-dependent fashion. The most potent derivatives, i.e. N6-isobutyl-PMEDAP, N6-cyclopentyl-PMEDAP, N6-cyclooctyl-PMEDAP, N6-dimethylaminoethyl-(R)-PMPDAP, N6-cyclopropyl-(R)-PMPDAP, and N6-cyclopentyl-(R)-PMPDAP are more effective than (R)-PMPA (tenofovir) itself. They exhibit immunostimulatory effects at concentrations as low as 1 to 5 microM. It is suggested that these compounds might be prospective candidates for antiviral therapeutic exploitation.
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PMID:Immunobiological activity of N-[2-(phosphonomethoxy)alkyl] derivatives of N6-substituted adenines, and 2,6-diaminopurines. 1295 71

It has been found that infection of target cells with the CC chemokine receptor 5-restricted (R5) human immunodeficiency virus type 1 (HIV-1) isolate requires the presence of CD4 and CCR5 molecules on the surface of target cells. We observed that R5 HIV-1 primary isolates from long term survivors replicate less efficiently than the same variants from AIDS progressors in Th1 and Th2 lymphocytes. Real-time quantitative polymerase chain reaction (RQ-PCR) of reverse transcribed messenger RNA, revealed approximately 2 times higher level of CCR5 transcript in Th1 than Th2 cells. Nevertheless we found that R5 HIV-1 primary isolates from long-term survivors and AIDS progressors replicated more efficiently in Th2 than Th1 lymphocytes. These findings correlated with lower-level biosynthesis of regulated upon activation, normal T-cell expressed and secreted (RANTES), and macrophage inflammatory protein-1alpha and -1beta (MIP-1alpha, MIP-1beta), in Th2 than Th1 lymphocytes. Our data indicates that Th0/Th2 cell orientation in HIV-infected individuals and a higher replication of R5 HIV-1 primary isolates in AIDS progressors than long term-survivors can be associated with progression to AIDS.
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PMID:Increased in vitro replication of CC chemokine receptor 5-restricted human immunodeficiency virus type 1 primary isolates in Th2 lymphocytes may correlate with AIDS progression. 1500 May 59

Wasting and renal diseases are frequent complications of HIV (human immunodeficiency virus) infection and are associated with accelerated disease progression and increased mortality. Transgenic mice expressing HIV1 under control of the CD4 promoter develop an AIDS-like disease and were used in the present work to study HIV1-induced wasting and kidney pathology. In this study, we reported that disease evolution paralleled increases in serum urea and creatinine levels, indicating an early and progressive deterioration of kidney function; meanwhile the wasting syndrome characterized by up-regulation of the ubiquitine-proteasome pathway and increased level of serum 3-methyl-histidine levels occurred at later stages just prior to death. Further examination of kidney and muscle pathologies revealed a progressive accumulation of CD45(+) cells, first affecting the kidneys. In addition, the onset of disease is accompanied by elevated levels of circulating "regulated on activation, normal and secreted T cell expressed and secreted" (RANTES). These results prompted us to assess the effects of AS602868, a specific small molecule inhibitor of IkappaB kinase 2 (IKK2) on disease progression. Inhibition of the NF-kappaB pathway indeed resulted in increased lifespan, kidney and lean body mass preservation. These beneficial results were associated with a reduction of CD45(+) cells infiltrating the kidneys, amelioration of the renal architecture, and reduced level of circulating RANTES. Together our data provide evidence that IKK2 inhibitors have therapeutic relevance in the treatment of HIV1-associated disorders.
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PMID:IKK2 inhibitor alleviates kidney and wasting diseases in a murine model of human AIDS. 1503 14

Topical microbicides that effectively block interactions between CCR5(+) immature Langerhans cells (LC) residing within genital epithelia and R5 human immunodeficiency virus (HIV) may decrease sexual transmission of HIV. Here, we investigated the ability of synthetic RANTES analogues (AOP-, NNY-, and PSC-RANTES) to block R5 HIV infection of human immature LC by using a skin explant model. In initial experiments using activated peripheral blood mononuclear cells, each analogue compound demonstrated marked antiviral activity against two R5 HIV isolates. Next, we found that 20-min preincubation of skin explants with each RANTES analogue blocked R5 HIV infection of LC in a dose-dependent manner (1 to 100 nM) and that PSC-RANTES was the most potent of these compounds. Similarly, preincubation of LC with each analogue was able to block LC-mediated infection of cocultured CD4(+) T cells. Competition experiments between primary R5 and X4 HIV isolates showed blocking of R5 HIV by PSC-RANTES and no evidence of increased propagation of X4 HIV, data that are consistent with the specificity of PSC-RANTES for CCR5 and the CCR5(+) CXCR4(-) phenotype of immature LC. Finally, when CCR5 genetic polymorphism data were integrated with results from the in vitro LC infection studies, PSC-RANTES was found to be equally effective in inhibiting R5 HIV in LC isolated from individuals with CCR5 diplotypes known to be associated with low, intermediate, and high cell surface levels of CCR5. In summary, PSC-RANTES is a potent inhibitor of R5 HIV infection in immature LC, suggesting that it may be useful as a topical microbicide to block sexual transmission of HIV.
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PMID:PSC-RANTES blocks R5 human immunodeficiency virus infection of Langerhans cells isolated from individuals with a variety of CCR5 diplotypes. 1522 Apr 35

Recent evidence suggests that injection drug users who abuse heroin are at increased risk of CNS complications from human immunodeficiency virus (HIV) infection. Opiate drugs may intrinsically alter the pathogenesis of HIV by directly modulating immune function and by directly modifying the CNS response to HIV. Despite this, the mechanisms by which opiates increase the neuropathogenesis of HIV are uncertain. In the present study, we describe the effect of morphine and the HIV-1 protein toxin Tat(1-72) on astroglial function in cultures derived from ICR mice. Astroglia maintain the blood-brain barrier and influence inflammatory signaling in the CNS. Astrocytes can express mu-opioid receptors, and are likely targets for abused opiates, which preferentially activate mu-opioid receptors. While Tat alone disrupts astrocyte function, when combined with morphine, Tat causes synergistic increases in [Ca(2+)](i). Moreover, astrocyte cultures treated with morphine and Tat showed exaggerated increases in chemokine release, including monocyte chemoattractant protein-1 (MCP-1) and regulated on activation, normal T cell expressed and secreted (RANTES), as well as interleukin-6 (IL-6). Morphine-Tat interactions were prevented by the mu-opioid receptor antagonist beta-funaltrexamine, or by immunoneutralizing Tat(1-72) or substituting a nontoxic, deletion mutant (Tat(Delta31-61)). Our findings suggest that opiates may increase the vulnerability of the CNS to viral entry (via recruitment of monocytes/macrophages) and ensuing HIV encephalitis by synergistically increasing MCP-1 and RANTES release by astrocytes. The results further suggest that astrocytes are key intermediaries in opiate-HIV interactions and disruptions in astroglial function and inflammatory signaling may contribute to an accelerated neuropathogenesis in HIV-infected individuals who abuse opiates.
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PMID:Synergistic increases in intracellular Ca2+, and the release of MCP-1, RANTES, and IL-6 by astrocytes treated with opiates and HIV-1 Tat. 1563 Jul 4

Human monocytes/macrophages (M/M) are the major targets for human immunodeficiency virus type 1 (HIV-1) infection. To characterize the global effects of acute HIV-1 infection on gene expression in M/M, the expression levels of 550 host cell RNA transcripts in U937 human promonocytes at 2-3 days after HIV-1 infection were assessed using cDNA microarray analysis and were compared to those in the infected HUT78, a CD4+ T cell line. Confirmed by semiquantitative RT-PCR, our results showed that 12 genes were up-regulated and 26 genes were down-regulated in the infected U937 cells at 2-3 days post-infection, whereas 8 genes were up-regulated and 20 genes were down-regulated in the infected HUT78 cells at 2-3 days post-infection. These genes encode a host of proteins with divergent functions in a variety of cellular processes including apoptosis (FAS, Fas ligand, PIN, HSP90beta, bcl-2, bcl-x), cell signal transduction (Ras, RGS1, IRF-1, STAT3), receptor-mediated signaling transduction (CD71, CD69, CD3delta), cell cycle and growth (c-myc, cytokines, kinase), transcriptional regulation (EWS, CREB-2), and chemotaxis (beta-chemokines, RANTES), supporting the general effects of HIV-1 infection on cells of different origin. Although most identified genes were regulated similarly in both infected cell lines, differences in gene regulation, such as c-myc, CD71, CD69, and beta-chemokines, between the two infected cell lines were also identified in this study. These differences may further our understanding of the pathogenicity of HIV and enable the discovery of novel therapeutic approach for AIDS.
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PMID:HIV-1 infection initiates changes in the expression of a wide array of genes in U937 promonocytes and HUT78 T cells. 1588 42


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