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 (chemoattractant cytokines) and their receptors are present in the brain and may play roles in both neurodevelopment and neuropathology. Increased brain levels of monocyte chemoattractant protein-1 (MCP-1), also known as CCL2, are found in patients with human immunodeficiency virus type 1 (HIV-1)-associated dementia and other acute and chronic neurologic diseases. Although the function of CCL2 in the brain is unclear, it is believed that upregulation of this chemokine during neuropathologic or neuroinflammatory conditions leads to recruitment of activated monocytes into the brain, where they differentiate into macrophages producing neurotoxic and inflammatory molecules. We recently showed that human fetal brain-derived progenitor cells are susceptible to HIV-1 and JC virus infection, and that differentiation toward an astrocyte phenotype increased virus production from these cells. In the current study, we found that in the absence of infection, progenitors produced moderate levels of CCL2 (5.6 ng per million cells). Astrocyte differentiation over 3 weeks increased CCL2 protein levels 30-fold in a biphasic manner, whereas neuronal differentiation decreased production 20-fold. Electromobility shift assays (EMSAs) demonstrated increased nuclear NF-kappaB levels within 2 h of initiating astrocyte differentiation, and inhibitors of NF-kappaB activation partially blocked the CCL2 increase in differentiating astrocytes. Transfection of progenitors with mutated CCL2 promoter/CAT reporter constructs showed that the distal promoter region, containing NF-kappaB and NF-I binding sites, is important for differentiation-induced CCL2 upregulation. Together these results suggest that the transcription factor NF-kappaB, and possibly NF-I, contribute to the upregulation of CCL2 chemokine production during the differentiation of human progenitor cells toward an astrocyte phenotype.
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PMID:Astrocyte differentiation selectively upregulates CCL2/monocyte chemoattractant protein-1 in cultured human brain-derived progenitor cells. 1620 98

Encephalitis and dementia associated with acquired immunodeficiency syndrome (AIDS) are characterized by leukocyte infiltration into the CNS, microglia activation, aberrant chemokine expression, blood-brain barrier (BBB) disruption, and eventual loss of neurons. Little is known about whether human immunodeficiency virus 1 (HIV-1) infection of leukocytes affects their ability to transmigrate in response to chemokines and to alter BBB integrity. We now demonstrate that HIV infection of human leukocytes results in their increased transmigration across our tissue culture model of the human BBB in response to the chemokine CCL2, as well as in disruption of the BBB, as evidenced by enhanced permeability, reduction of tight junction proteins, and expression of matrix metalloproteinases (MMP)-2 and MMP-9. HIV-infected cells added to our model did not transmigrate in the absence of CCL2, nor did this condition alter BBB integrity. The chemokines CXCL10/interferon-gamma-inducible protein of 10 kDa, CCL3/macrophage inflammatory protein-1alpha, or CCL5/RANTES (regulated on activation normal T-cell expressed and secreted) did not enhance HIV-infected leukocyte transmigration or BBB permeability. The increased capacity of HIV-infected leukocytes to transmigrate in response to CCL2 correlated with their increased expression of CCR2, the chemokine receptor for CCL2. These data suggest that CCL2, but not other chemokines, plays a key role in infiltration of HIV-infected leukocytes into the CNS and the subsequent pathology characteristic of NeuroAIDS.
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PMID:CCL2/monocyte chemoattractant protein-1 mediates enhanced transmigration of human immunodeficiency virus (HIV)-infected leukocytes across the blood-brain barrier: a potential mechanism of HIV-CNS invasion and NeuroAIDS. 1643 95

Cell-to-cell contact between monocyte-derived macrophages (MDM) and endothelial cells has resulted in the increased proliferation of CC chemokine receptor 5/M-tropic (R5) human immunodeficiency virus (HIV) in MDM. In the present study, R5 HIV replication was shown to be increased by polymorphonuclear neutrophils (PMN) in MDM cultures through the soluble factors released from these PMN. The replication of R5 HIV in MDM was greatly enhanced when PMN were added to cultures. An increase in the replication of R5 HIV was also demonstrated when the virus was replicated in MDM cultured in a double chamber transwell with PMN. Chemokine ligand (CCL) 2 and interleukin (IL)-10 were detected in culture fluids of PMN exposed to R5 HIV. The replication of R5 HIV was not accelerated in cultures of MDM and PMN in a double chamber transwell supplemented with a mixture of monoclonal antibodies directed against CCL2 and IL-10. Similarly, the replication of R5 HIV was accelerated in MDM cultures supplemented with a mixture of recombinant CCL2 and IL-10. These results indicated that, in response to the viral stimulation, PMN produce CCL2 and IL-10 and enhance the replication of R5 HIV in MDM cultures.
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PMID:Acceleration of R5 HIV replication by polymorphonuclear neutrophils in cultures of macrophages. 1721 33

Over 50% of all human immunodeficiency virus type 1 (HIV-1) infections worldwide are caused by subtype C strains, yet most research to date focuses on subtype B, the subtype most commonly found in North America and Europe. The HIV-1 trans-acting regulatory protein (Tat) is essential for regulating productive replication of HIV-1. Tat is secreted by HIV-infected cells and alters several functions of uninfected bystander cells. One such function is that, by acting at the cell membrane, subtype B Tat stimulates the production of tumor necrosis factor (TNF) and chemokine (C-C motif) ligand 2 (CCL2) from human monocytes and can act as a chemoattractant. In this study, we show that the mutation of a cysteine to a serine at residue 31 of Tat commonly found in subtype C variants significantly inhibits the abilities of the protein to bind to chemokine (C-C motif) receptor 2 (CCR2), induce intracellular calcium flux, stimulate TNF and CCL2 production, and inhibit its chemoattractant properties. We also show that TNF is important in mediating some effects of extracellular Tat. This report therefore demonstrates the important functional differences between subtype C and subtype B Tat and highlights the need for further investigation into the different strains of HIV-1.
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PMID:Human immunodeficiency virus type 1 subtype C Tat fails to induce intracellular calcium flux and induces reduced tumor necrosis factor production from monocytes. 1737 3

Monocytes and macrophages play a central role in the pathogenesis of human immunodeficiency virus (HIV)-associated dementia. They represent prominent targets for HIV infection and are thought to facilitate viral neuroinvasion and neuroinflammatory processes. However, many aspects regarding monocyte brain recruitment in HIV infection remain undefined. The nonhuman primate model of AIDS is uniquely suited for examination of the role of monocytes in the pathogenesis of AIDS-associated encephalitis. Nevertheless, an approach to monitor cell migration from peripheral blood into the central nervous system (CNS) in primates had been lacking. Here, upon autologous transfer of fluorescein dye-labeled leukocytes, we demonstrate the trafficking of dye-positive monocytes into the choroid plexus stromata and perivascular spaces in the cerebra of rhesus macaques acutely infected with simian immunodeficiency virus between days 12 and 14 postinfection (p.i.). Dye-positive cells that had migrated expressed the monocyte activation marker CD16 and the macrophage marker CD68. Monocyte neuroinvasion coincided with the presence of the virus in brain tissue and cerebrospinal fluid and with the induction of the proinflammatory mediators CXCL9/MIG and CCL2/MCP-1 in the CNS. Prior to neuroinfiltration, plasma viral load levels peaked on day 11 p.i. Furthermore, the numbers of peripheral blood monocytes rapidly increased between days 4 and 8 p.i., and circulating monocytes exhibited increased functional capacity to produce CCL2/MCP-1. Our findings demonstrate acute monocyte brain infiltration in an animal model of AIDS. Such studies facilitate future examinations of the migratory profile of CNS-homing monocytes, the role of monocytes in virus import into the brain, and the disruption of blood-cerebrospinal fluid and blood-brain barrier functions in primates.
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PMID:Neuroinvasion of fluorescein-positive monocytes in acute simian immunodeficiency virus infection. 1771 37

In this second review on chemokines, we focus on the polymorphisms and alternative splicings and on their consequences in disease. Because chemokines are key mediators in the pathogenesis of inflammatory, autoimmune, vascular and neoplastic disorders, a large number of studies attempting to relate particular polymorphisms of chemokines to given diseases have already been conducted, sometimes with contradictory results. Reviewing the published data, it becomes evident that some chemokine genes that are polymorphic have alleles that are found repeatedly, associated with disease of different aetiologies but sharing some aspects of pathogenesis. Among CXC chemokines, single nucleotide polymorphisms (SNPs) in the CXCL8 and CXCL12 genes stand out, as they have alleles associated with many diseases such as asthma and human immunodeficiency virus (HIV), respectively. Of CC chemokines, the stronger associations occur among alleles from SNPs in CCL2 and CCL5 genes and a number of inflammatory conditions. To understand how chemokines contribute to disease it is also necessary to take into account all the isoforms resulting from differential splicing. The first part of this review deals with polymorphisms and the second with the diversity of molecular species derived from each chemokine gene due to alternative splicing phenomena. The number of molecular species and the level of expression of each of them for every chemokine and for each functionally related group of chemokines reaches a complexity that requires new modelling algorithms akin to those proposed in systems biology approaches.
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PMID:The chemokine network. II. On how polymorphisms and alternative splicing increase the number of molecular species and configure intricate patterns of disease susceptibility. 1784 70

Human immunodeficiency virus (HIV) infection is associated with accelerated atherosclerosis and vasculopathy, although the mechanisms underlying these findings have not been determined. Hypotheses for these observations include: 1) an increase in the prevalence of established cardiac risk factors observed in HIV-infected individuals who are currently experiencing longer life expectancies; 2) the dyslipidemia reported with certain HIV anti-retroviral therapies; and/or 3) the proinflammatory effects of infiltrating HIV-infected monocytes/macrophages. An unexplored possibility is whether HIV itself can infect vascular smooth muscle cells (SMCs) and, by doing so, whether SMCs can accelerate vascular disease. Our studies demonstrate that human SMCs can be infected with HIV both in vivo and in vitro. The HIV protein p24 was detected by fluorescence confocal microscopy in SMCs from tissue sections of human atherosclerotic plaques obtained from HIV-infected individuals. Human SMCs could also be infected in vitro with HIV by a mechanism dependent on CD4, the chemokine receptors CXCR4 or CCR5, and endocytosis, resulting in a marked increase in SMC secretion of the chemokine CCL2/MCP-1, which has been previously shown to be a critical mediator of atherosclerosis. In addition, SMC proliferation appeared concentric to the vessel lumen, and minimal inflammation was detected, unlike typical atherosclerosis. Our data suggest that direct infection of human arterial SMCs by HIV represents a potential mechanism in a multifactorial paradigm to explain the exacerbated atherosclerosis and vasculopathy reported in individuals infected with HIV.
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PMID:Human immunodeficiency virus (HIV) infects human arterial smooth muscle cells in vivo and in vitro: implications for the pathogenesis of HIV-mediated vascular disease. 1831 May 3

In this cross-sectional study, we sought to determine whether gene expression of macrophage markers and inflammatory chemokines in lipoatrophic subcutaneous abdominal adipose tissue and liver fat content are increased and interrelated in human immunodeficiency virus (HIV)-1-positive, highly active antiretroviral therapy (HAART)-treated patients with lipodystrophy (HAART+LD+; n = 27) compared with those without (HAART+LD-; n = 13). The study groups were comparable with respect to age, gender, and body mass index. The HAART+LD+ group had twofold more intra-abdominal (P = 0.01) and 1.5-fold less subcutaneous (P = 0.091) fat than the HAART+LD- group. As we have reported previously, liver fat was 10-fold higher in the HAART+LD+ compared with the HAART+LD- group (P = 0.00003). Inflammatory gene expression was increased in HAART-lipodystrophy: CD68 4.5-fold (P = 0.000013), tumor necrosis factor (TNF)-alpha 2-fold (P = 0.0094), chemokine (C-C motif) ligand (CCL) 2 2.5-fold (P = 0.0024), CCL3 7-fold (P = 0.0000017), integrin alphaM (ITGAM) 3-fold (P = 0.00067), epidermal growth factor-like module containing, mucin-like, hormone receptor-like (EMR)1 2.5-fold (P = 0.0038), and a disintegrin and metalloproteinase domain (ADAM)8 3.5-fold (P = 0.00057) higher in the HAART+LD+ compared with the HAART+LD- group. mRNA concentration of CD68 (r = 0.37, P = 0.019), ITGAM (r = 0.35, P = 0.025), CCL2 (r = 0.39, P = 0.012), and CCL3 (r = 0.54, P = 0.0003) correlated with liver fat content. In conclusion, gene expression of markers of macrophage infiltration and adipose tissue inflammation is increased in lipoatrophic subcutaneous abdominal adipose tissue of patients with HAART-associated lipodystrophy compared with those without. CD68, ITGAM, CCL2, and CCL3 expression is significantly associated with accumulation of liver fat.
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PMID:Adipose tissue inflammation and liver fat in patients with highly active antiretroviral therapy-associated lipodystrophy. 1843 Sep 64

Monocyte infiltration is an important pathogenic event in human immunodeficiency virus type one (HIV-1) associated dementia (HAD). CXCL8 (Interleukin 8, IL-8), a CXC chemokine that elicits chemotaxis of neutrophils, has recently been found to recruit monocytes or synergistically enhance CCL2-mediated monocyte migration. In this report, we demonstrate CXCL8 levels in the cerebrospinal fluid of HAD patients are higher than HIV-1 seropositive patients without neurological impairment. The underlying mechanisms regulating CXCL8 production during disease are not completely understood. We investigated the role of HIV-1-infected and immune-competent macrophages, the principal target cell and mediator of neuronal injury in HAD, in regulating astrocyte CXCL8 production. Immune-activated and HIV-1-infected human monocyte-derived-macrophages (MDM) conditioned media (MCM) induced production of CXCL8 by human astrocytes. This CXCL8 production was dependent on MDM IL-1beta and TNF-alpha production following viral and immune activation. CXCL8 production was reduced by inhibitors for mitogen-activated protein kinases (MAPKs), including p38, c-Jun N-terminal kinase (JNK), and extracellular signal-regulated kinases (ERK1/2). Moreover, prolonged IL-1beta or TNF-alpha treatment activated double-stranded RNA-activated protein kinase (PKR). Inhibition of PKR prevented elevated CXCL8 production in astrocytes. We conclude that IL-1beta and TNF-alpha, produced from HIV-1-infected and immune-competent macrophages, are critical in astrocyte CXCL8 production. Multiple protein kinases, including p38, JNK, ERK1/2, and PKR, participate in the inflammatory response of astrocytes. These observations will help to identify effective therapeutic strategies to reduce high-levels of CXCL8-mediated CNS inflammation during HAD.
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PMID:HIV-1-infected and/or immune-activated macrophages regulate astrocyte CXCL8 production through IL-1beta and TNF-alpha: involvement of mitogen-activated protein kinases and protein kinase R. 1865 46

Peroxisome proliferator-activated receptors (PPARs) are nuclear receptors which down-regulate inflammatory signaling pathways. Therefore, we hypothesized that alterations of PPAR functions can contribute to human immunodeficiency virus-1 (HIV-1)-induced dysfunction of brain endothelial cells. Indeed, treatment with HIV-1 transactivator of transcription (Tat) protein decreased PPAR transactivation in brain endothelial cells. We next stably over-expressed PPARalpha and PPARgamma in a newly developed cell line of human brain endothelial cells (hCMEC/D3 cells). Tat-induced up-regulation of inflammatory mediators, such as interleukin (IL)-1beta, tumor necrosis factor-alpha, CCL2, and E-selectin were markedly attenuated in hCMEC/D3 over-expressing PPARalpha or PPARgamma. These results were confirmed in CCL2 and E-selectin promoter activity studies. Similar protective effects were observed in hCMEC/D3 after activation of PPARgamma by exogenous PPAR agonists (dPGJ(2) and rosiglitazone). PPAR over-expression also prevented Tat-induced binding activity and transactivation of nuclear factor-kappaB. Importantly, increased PPAR activity attenuated induction of IL-1beta, tumor necrosis factor-alpha, CCL2, and E-selectin in hCMEC/D3 cells co-cultured with HIV-1-infected Jurkat cells. The protective effects of PPAR over-expression were reversed by the antagonists of PPARalpha (MK886) or PPARgamma (GW9662). The present data suggest that targeting PPAR signaling may provide a novel therapeutic approach to attenuate HIV-1-induced local inflammatory responses in brain endothelial cells.
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PMID:PPARalpha and PPARgamma effectively protect against HIV-induced inflammatory responses in brain endothelial cells. 1871 Apr 15


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