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• W2324194497 abstract "Introduction: chemokines and chemokine receptors Chemokines (chemo tactic cyto kines) are a family of small (7–10 kDa), structurally related, highly basic proteins, principally known for their ability to induce migration and activation of specific leukocyte populations. Chemokines have been found in mammals, birds, and fish; sequence homologies across these diverse species indicate some evolutionary conservation. They are produced by many different cell types and play important roles in normal and diseased states such as: (i) control of immune cell trafficking and circulation of leukocytes between blood vessels, lymph, lymphoid organs and tissues; (ii) host immune surveillance and acute and chronic inflammatory responses; (iii) cell adhesion, phagocytosis, and cytokine secretion; (iv) regulation of angiogenesis, cellular proliferation and apoptosis; and (v) viral pathogenesis [1–5]. Aberrant regulation of chemokine expression is also associated with some chronic inflammatory conditions such as arthritis, atherogenesis, and glomerulonephritis [6–10]. All of these functions are performed through their interaction with specific low- and high-affinity receptors on the surface of target hematopoietic and nonhematopoietic cells. The chemokine family contains more than 50 members classified into four subfamilies (CXC, CC, C and CX3C, or α, β, γ and δ, respectively) named according to the number and spacing of the conserved cysteines near their amino-termini (Fig. 1). Members of each subfamily resemble each other more than members of other subfamilies, but this classification has only very general functional correlations. However, among the CXC chemokines, those containing a tripeptide glutamic acid–leucine–arginine (ELR) motif in their amino-terminal domain (IL-8, GRO or ENA-78) generally show specificity for neutrophil chemotaxis and activation, and are potent inducers of angiogenesis [11–14], whereas non-ELR CXC chemokines (IP-10, MIG or SDF-1) are chemoattractants for lymphocytes and monocytes and with one exception [15] do not induce angiogenesis. Members of the CC subfamily attract monocytes, basophils, eosinophils, and T lymphocytes, but have little or no effect on neutrophils. Both the CXC and CC groups contain many members while the C and CX3C subfamilies each contain only one member, lymphotactin [16] and fractalkine [17,18], respectively. Uniquely among the known chemokines, fractalkine exists in both soluble and membrane-bound forms [19–21] and it has an atypical constitutive expression in non-hematopoietic tissues such as the brain [22–24], endothelial cells [19,25], kidney, lung, and heart. Together with its receptor, fractalkine has been the focus of a number of studies because of its important role in inflammation and homeostasis.Fig. 1.: Structural classification of the chemokine family of proteins. C, Cysteine; X, an amino acid other than cysteine; dots indicate other amino acids; underlining indicates gaps in the sequence alignment.The chemokine receptors belong to the seven-transmembrane domain receptor superfamily of molecules that mediate intracellular signals through heterotrimeric GTP-binding proteins, also known as G-protein-coupled receptors. They are composed of a single 340–370 amino acid long polypeptide chain. The G-protein-coupled receptors have a relatively short, acidic amino-terminal segment with tyrosine residues that may be sulfated, potential N-linked glycosylation sites, a cysteine in each of the four extracellular regions (the amino-terminal and three extracellular loops or ECL) and several serines and threonines in their carboxy-terminal tails. The latter are phosphorylated after the receptor–ligand interaction. The hypothetical configuration of a chemokine receptor within a lipid bilayer is shown in Fig. 2 (amino acid residues shown are those of human CCR5). As nearly all of the chemokine receptors are selective for one class of chemokines, their names reflect their chemokine ligands and the numbers indicate the specific chemokine involved (e.g., CCR1-11, CXCR1-5, XCR1 and CX3CR1). Upon ligand binding all chemokine receptors activate G proteins for signal transduction. Although there is some heterogeneity in the specific members of the G protein family engaged by each receptor, most of them are members of the Bordetella pertussis toxin-sensitive subfamily of G proteins [26,27]. G proteins trigger a cascade of events that includes activation of phospholipase Cβ2, subsequent cleavage of phosphatidylinositol 4,5-biphosphate, and formation of second messengers such as phosphatidylinositol 1,4,5-triphosphate (which mobilizes calcium from intracellular stores) and diacyl-glycerol (which acts together with calcium to activate various isoforms of protein kinase C) [28–31].Fig. 2.: Hypothetical representation of a chemokine receptor within the plasma membrane. Amino acid sequence shown is that of human CCR5. Conserved cysteines and potential disulfide bonds in the extracellular regions (amino-terminal domain and extracellular loops [ECL] 1, 2 and 3) are shown in pink; putative phosphorylation sites in the carboxy-terminal domain (serine and threonine residues) are shown in yellow.Cellular responses are mediated by chemokines through the calcium-induced activation of protein kinase C and other calcium-sensitive protein kinases that catalyze protein phosphorylation as well as subsequent more distal events. Several chemokines have been reported to activate the mitogen-activated protein kinase (MAPK) cascade, especially, but not exclusively, the pathway involving activation of ERK1/2 [29,31–36] and the calcium-dependent protein kinase Pyk2 [32,34,37]. Finally, the phosphoinositide 3-kinase (PI3-K) and the subsequent activation of protein kinase B have been also described as a pathway activated by many chemokines [32,38–41]. For example, the treatment of hippocampal neurons with fractalkine has been reported to enhance neuronal survival through a PI3-K-mediated regulation of nuclear factor-κB activity [42]. The phosphorylation of the serine and threonine residues in the carboxy-terminal region of the chemokine receptor, together with receptor sequestration by internalization, are probably the mechanisms by which the cells become partially or totally desensitized to the repeated stimulation by the same or other agonist using the same receptor. Multimerization has been reported for some chemokine receptors such as CXCR4, CCR2 and CCR5 [43–48]. It seems that dimerization is a consequence of chemokine binding and is required for signaling. In addition, chemokine receptor dimerization may have important effects on cellular susceptibility to HIV-1 infection [46,49]. The relationships between chemokines and chemokine receptors are complex, and reflect some redundancy in the system, as individual chemokine receptors may bind multiple chemokines within a class and many chemokines can bind to more than one chemokine receptor (summarized in Table 1). However, there are some unique ligand–receptor interactions such as SDF-1 with CXCR4, lymphotactin with XCR1 or fractalkine with CX3CR1. Their expression has been extensively studied in cells of hematopoietic origin, because of the key role of these molecules in the immune system and the inflammatory responses (Table 1).Table 1: Summary of known chemokine ligands, and systemic and brain-specific cellular distribution, of chemokine receptors. Chemokines and chemokine receptors in the brain A growing number of studies have addressed the expression patterns of chemokines and chemokine receptors in the central nervous system (CNS) and, in particular the brain, where astrocytes, microglial cells and neurons are the main cell types implicated in this signaling network (Tables 1 and 2). All members of the CXCR type of receptors except CXCR1 are expressed in the CNS, primarily in different neuronal subpopulations. At the same time, their principal chemokine ligands are expressed by astrocytes (IL-8, GROα, IP-10) and neurons (MCP-1, GROα). More specifically, CXCR2 is expressed by subsets of neurons in several regions of the brain and spinal cord, as well as by astrocytes [50–53], and CXCR3 is constitutively expressed in astrocytes, microglia and neurons from various cortical and subcortical regions [51,54,55]. CXCR1 expression has been detected only in an astrocytic cell line infected by HIV-1 [52]. CXCR4 requires special attention because it is expressed by vascular endothelial cells, microglia, astrocytes, and neurons in both the central and peripheral nervous system [51–53,56–65] and its only ligand, SDF-1, is also widely expressed in the CNS by astrocytes, microglia, cortical neurons, and cerebellar granule cells [56,59] (Table 2). Coughlan et al. used a panel of monoclonal antibodies and RT–PCR and detected expression of CXCR2, CXCR3 and CXCR4 in human fetal neurons cultured from brain tissue and in the NT2.N human neuronal cell line [51]. Furthermore, neurons showed robust calcium transients after exposure to either SDF-1α or melanocyte growth-stimulating activity (CXCR2 ligand) [51]. Finally, CXCR5 is also expressed in neuronal tissues and cells [66].Table 2: Cellular sources of major chemokines in the brain and potential effects of its production. Expression of the CCR subfamily of chemokine receptors has been detected in the brain under both physiological and pathological conditions. They are found in inflammatory and neurodegenerative diseases such as multiple sclerosis (MS), Alzheimer's disease (AD) and in the neurological syndrome observed in some HIV-1-infected patients, known as HIV-associated dementia (HAD) or AIDS-dementia complex (ADC). CCR3 and CCR5 have been detected in both normal and inflamed brains, and these particular receptors are associated with various neuronal subsets, as well as microglia and astrocytes [53,58,61,64,65,67–69]. In an extensive study, van der Meer et al. showed that neurons and glial cells in the hippocampus and other regions of the brain expressed CCR2, CCR3 and CXCR4 but not CCR5, while microglial cells were positive for CCR5 [63]. Detection of other members of this subfamily such as CCR1, CCR4 or CCR8 has also been reported, primarily in hippocampal neurons and/or astrocytes [51,53,64,70,71]. At the same time, β-chemokines (e.g. RANTES, MIP-1α and 1β, etc.) are weakly expressed in normal brains (Table 2). Constitutive expression can be detected only at low levels, but their production appears to be increased in inflammatory conditions (see below and Table 2). However, MCP-1 release has been detected in cultures of NT2.N neurons but not of undifferentiated NT2 cells [51], and these results show that neurons themselves may release chemokines that may ultimately affect cellular function within the CNS. Finally, fractalkine, the most recently discovered chemokine in the CNS, is expressed there at higher levels than in the immune system. Neurons [22–24] and endothelial cells [19,25] are the main source of fractalkine, although within the CNS, it is also expressed by microglia and astrocytes [18,72] (Table 2). Its expression in these cells can be upregulated by TNF-α or IL-1β [72]. CX3CR1 is the exclusive receptor for fractalkine, and it interacts with either the membrane-anchored or soluble forms of the chemokine [19,64, 73]. Microglial cells express high levels of CX3CR1 and migrate in response to stimulation by soluble fractalkine [22,72]. There is also functional expression of CX3CR1, although at lower levels, in astrocytes [22,72] and in cultures of primary hippocampal neurons [42]. In addition to microglia and astrocytes, CX3CR1 is expressed as well in monocytes and in subsets of natural killer (NK) and dendritic cells. Thus, fractalkine can function as an adhesion molecule between endothelial and NK cells. Soluble fractalkine has also enhanced the cytolytic activity exhibited by NK cells against K562 target cells, indicating that it can play an important role in NK cell-mediated endothelial damage [74]. Fractalkine may thus participate in vascular damage, a role that may be crucial in the preservation or alteration of the blood–brain barrier. However, CX3CR1-defficient mice have shown no impairment in monocyte extravasation, dendritic cell migration and differentiation, or microglial response to peripheral nerve injury. These findings suggest that the neuronal–glial cross-talk is near normal in its absence [75], and perhaps that as with other chemokines, there is some redundancy in its function. Role of brain chemokines and chemokine receptors in normal physiologic activity As the key physiological role of the chemokine network is the regulation of leukocyte migration and function throughout the body, it is not surprising that this activity is one of several crucial roles that chemokines play within the CNS. Secretion of chemokines and expression of chemokine receptors in brain microvascular endothelial cells promotes the recruitment of hematopoietic cells from the circulation, both as part of normal surveillance and immunological control within the brain, and as a component of the inflammatory response during pathological processes. In addition to this obvious role in neuroimmunology, chemokines and chemokine receptors seem to play a physiological role in brain development and in the maintenance of normal brain homeostasis. Because of the need of chemoattractant factors for the migration of multipotent progenitor cells during development and the similarities between hematopoiesis and neuropoiesis, it is likely that chemokines influence CNS and brain development [76]. In this sense, it has been described that: (i) RANTES and SDF-1 elicit robust migratory and differentiation responses in human and/or murine neuronal cells [35,77,78]; (ii) CCR5 and CXCR4 are expressed and functional in human embryonic neurons, supporting the idea that they might play a role during brain ontogeny [79]; and (iii) SDF-1 and CXCR4 are probably very important for CNS development because mice lacking either of these genes have abnormal cerebellar development [80–83]. Furthermore, it is now also clear that chemokines play a role in the modulation of synaptic activity in the brain [53,84–86] and in the proliferative response of specific CNS cell types to several growth factors [32,87,88]. Role of chemokines and chemokine receptors on pathogenic processes in the brain Studies have also shown that chemokines and chemokine receptors play a significant role in the pathophysiology of inflammatory and neurodegenerative diseases such as head trauma, stroke, viral encephalitis, and MS. MS is a chronic inflammatory disease characterized by demyelination, focal T-cell and macrophage infiltration, glial cell activation, axonal injury and loss of neurological function [89,90]. Expression of chemokines such as MCP-1, IP-10, RANTES, MCP-3 and I-309 has been reported in the CNS of rats with experimental autoimmune encephalomyelitis (EAE) [91–94], an animal model for MS. Antibodies against MIP-1α and MCP-1 have inhibited both the initial establishment of EAE and its relapses [95–97]. In addition, increased expression of CCR2, CCR5, CXCR4, and CX3CR1 has been described in the spinal cords of animals with EAE [98]. Similarly, analysis of cerebrospinal fluid (CSF) and brain tissues from MS patients has demonstrated that the levels of IP-10, MIG and RANTES were increased in the CSF during MS relapses [99], while in the brain, MIP-1α expression was associated with glial cells, MIP-1β with macrophages/microglia, RANTES with perivascular leukocytes, and MCP-1 with macrophages and astrocytes in chronic active MS lesions (Table 2) [100,101]. With regard to receptor expression, several studies have shown that CXCR3 as well as CCR1, CCR2, CCR3 and CCR5 are highly expressed in different cell types of actively demyelinating MS lesions [99–101]. In fact, the beneficial effects of interferon-β in MS patients are probably related to the regulation of these relationships, as it has been demonstrated that this interferon inhibits the in vitro expression of RANTES and MIP-1α, as well as one of their receptors, CCR5, in cultures of T cells obtained from MS patients [102]. In addition, the down-regulation of MIP-1α itself may be also beneficial because mice lacking CCR1 (which is another receptor for this chemokine) are partially protected against induction of EAE [103]. As macrophages and microglia present within the MS plaques are immunoreactive for both CCR1 and MIP-1α, CCR1 may be an important therapeutic target. In AD, increased migration of inflammatory cells into the CNS has not been definitively demonstrated [104]. However, there is growing evidence on the contribution of upregulated expression of chemokines and chemokine receptors in the brain of AD patients to plaque-associated inflammation and neurodegeneration. In this sense, immunohistochemical analysis has shown CXCR2 expression on some dystrophic neurites in senile plaques [50,105] and many CCR3- and CCR5-reactive microglial cells and MIP-1β-reactive astrocytes in association with amyloid deposits [69]. In addition, expression of IP-10 in astrocytes from the brains of patients with AD is markedly increased over the constitutive expression in normal brains and is associated with the senile plaques and the upregulation of MIP-1β [54]. As neurons express the receptor for IP-10, CXCR3, this can be also a mechanism of neuronal–glial interaction implicated in the pathogenesis of AD. The function of chemokine receptors in HIV-1 infection Entry of HIV-1 into cells occurs through a series of events mediated by its envelope glycoproteins, the noncovalently associated gp120 and gp41, which are organized as trimers in the viral outer surface. The gp120 is heavily glycosylated [106–108] and is composed of five variable loops (V1–V5) and five more conserved regions (C1–C5) defining a core [109–113]; the gp41 contains a transmembrane domain and the fusion peptide that is inserted into the membrane of the target cells [114,115]. Binding to the primary receptor, CD4, involves a large region in gp120 and it is not sufficient for entry; however, it triggers a conformational change in gp120 that allows exposure of conserved regions previously folded into the core structure and hidden because of the variable loops and the carbohydrate moiety of the glycoprotein [116–124]. Among the variable loops, V1 and V2, but also V3, change conformation following CD4 binding [116,117,123,125], resulting in the exposure of conserved, discontinuous structures recognized by the 17b and 48d monoclonal antibodies [120,123,124]. The partial co-localization between the 17b and 48d epitopes and the gp120 structures important for chemokine receptor binding [111] supports a model in which the conformational change induced by CD4 binding allows the exposure of a high-affinity binding site for the coreceptor molecule [111,126,127]. Chemokine receptor binding induces a new conformational change leading to the formation of a trimeric coiled coil in gp41 which initiates the fusion-active structure in the complete envelope [128–132]. Recent data suggest that CD4 binding alone may be sufficient for this structure to form and the chemokine binding event would only increase the exposure of the hydrophobic fusion peptide present in the amino-terminal region of gp41 [132,133]. However, no viral envelope has been identified that is able to induce fusion in a CD4-dependent, coreceptor-independent manner. Thus, it can be concluded that coreceptor binding is critical for the fusion process. The insertion of the fusion peptide into the target cell membrane induces the formation of an intermediate form called a six-helix bundle in which the two lipid bilayers come into close proximity and eventually fuse. This activity allows the viral nucleocapsid to enter into the cell [132,133]. These final steps in the process of HIV-1 entry into cells are still not completely understood. The first chemokine receptor found to function as a coreceptor for HIV-1 entry was CXCR4 [134–136], but it mediated infection only by those isolates with specific tropism for T cells and T-cell lines. Shortly after that, CCR5 was also reported to mediate this process for the other major viral phenotype: isolates with specific tropism for macrophages [137–141]. CCR5 and/or CXCR4 have been shown to support virus entry for the vast majority of primary HIV-1 isolates tested, and their use by HIV has been correlated with some biological properties [142–146]. However, other chemokine receptors such as CCR2, CCR3, CCR8, CCR9 or CX3CR1, as well as several orphan receptors (such as STRL33/BONZO, GPR1, GPR15/BOB and APJ) have been shown to function as coreceptors for HIV-1 infection [71,73,138,140,147–153]. Coreceptor usage by HIV-1, HIV-2, and SIV is summarized in Table 3. Each of these alternative coreceptors for HIV-1 can function to some extent in vitro for virus entry or envelope-mediated cell–cell fusion. It is yet unclear, however, how they function in vivo, and whether they have an impact on viral tropism and pathogenesis. Potentially, the use of coreceptors other than CCR5 or CXCR4 could enable virus strains to infect a wider spectrum of cell types, including some in the nervous system (e.g., neurons, astrocytes, oligodendrocytes), thymus, or mucosal surfaces.Table 3: Chemokine and orphan receptors expressed in the brain which can be used as receptors/coreceptors by HIV and SIV for fusion/entry into cells. The gp120 V3 region plays an important role in the interaction between gp120 and chemokine receptors [154–163]. Recent experiments have provided additional insights into this binding, allowing the development of a model in which the coreceptor interacts with V3 and with a conserved region named ‘bridging sheet’ composed of the V1/V2 stem and an antiparallel, four-stranded structure containing residues located in the C4 region of gp120 [109,111–113,164]. With respect to the coreceptor, all extracellular domains have been implicated to some extent in this interaction although the amino-terminal region and the ECL2 appear to play a key role [140,155,165–190]. In this regard, at least with respect to the binding between CCR5 and the gp120 of R5-using viruses, the amino-terminal region has been proposed to mediate the initial contact to gp120, while a subsequent binding to the ECL2 seems to be crucial for fusion to take place. Fig. 3 shows an analysis of the efficiency of interaction between two slightly different envelopes incorporated into luciferase-containing pseudotypes, and CCR5, CCR2b or several chimeric receptors, transiently expressed on cells together with CD4, by measuring the entry of pseudotypes as determined by luciferase activity in the target cells [191].Fig. 3.: Analysis of the relationship between CCR5 and the envelope glycoproteins of two closely related viruses [191]. The study was performed using envelope-pseudotyped luciferase viruses to infect cells expressing CD4 alone or plus: wild-type CCR5 or CCR2b; CCR5 molecules with a deletion of the last 4, 8 or 12 residues in the amino-terminal domain (D4, D8 and D12, respectively); and CCR5/CCR2b chimeric receptors containing either a single extracellular domain of CCR5 in the context of CCR2b (5222, 2522, 2252 and 2225, where each number designates in order the amino-terminal domain and the ECL1, ECL2, and ECL3 of the receptor molecule), or a single extracellular domain of CCR2b in the context of CCR5 (named 2555, 5255, 5525 and 5552), or the amino-terminal domain and ECL2 of CCR5 together with the ECL1 and ECL3 of CCR2b (named 5252). All chimeric constructions were kindly provided by J. Rucker and R. W. Doms, University of Pennsylvania. The results (mean relative light units per second of five to seven experiments + SD) show that very few amino acid differences in the envelope gp120 can modify considerably its relationship with the chemokine receptor, apparently by altering the interaction with individual extracellular domains in the receptor molecule. Asterisks indicate a statistically significant difference.Given the important phenotypic attributes ascribed to CCR5 and CXCR4 use, and the findings that virtually all HIV isolates can use one or both of these coreceptors, viral isolates have been classified as R5 or macrophage (M)-tropic, X4 or T-cell-tropic, and R5X4 or dual-tropic viruses. R5 or M-tropic viruses infect macrophages and primary CD4 T cells via CCR5 (Fig. 4); most R5 isolates do not infect T-cell lines because they usually do not express CCR5. Some T-cell lines, however, may have extremely low levels of CCR5 expression that support infection by some particular, highly efficient R5 isolates [192]. X4 or T-tropic viruses infect primary CD4 T cells and T-cell lines via CXCR4, as well as macrophages, which express low levels of CXCR4. Finally, R5X4, otherwise referred to as dual-tropic viruses, can infect all macrophages, primary CD4 T cells and T-cell lines via either CCR5 or CXCR4 (see Fig. 4 for a summary). Remarkably, R5 or macrophage-tropic viruses are most often found in the acute phase of the infection suggesting selective transmission across mucosal surfaces although this dominance could reflect preferential growth of R5 virus in primary infection. Dual-tropic or T-tropic isolates generally appear later in the course of infection. Furthermore, R5 isolates are often less cytopathic than X4 viruses. This observation led to the R5 isolates being initially classified as nonsyncytium-inducing, and X4 viruses as syncytium-inducing. Finally, there is a clear relationship between coreceptor usage, transmission of infection, and disease evolution. As noted above, macrophage-tropic or R5 viruses are found predominantly in patients with recent infection. However, in later stages of the disease process, in an important subset of patients though not in all, increased viral load and decreased CD4 cell count takes place concurrently with the appearance of R5X4 and/or X4 viruses [193].Fig. 4.: Model for coreceptor usage and HIV-1 tropism. X4- or T-tropic strains bind specifically to CXCR4 and can infect continuous CD4 T-cell lines and primary CD4 T cells, or rarely, depending on the strain, some macrophages. R5- or macrophage-tropic strains bind specifically to CCR5 and thus can infect primary macrophages and primary CD4 T-cells, while only few strains can infect CD4 T-cell lines. R5X4- or dual-tropic strains bind to both CCR5 and CXCR4 and can infect primary macrophages, primary CD4 T cells and CD4 T-cell lines. Similar to primary macrophages, microglia can be infected by macrophage-tropic and dual-tropic viruses, but only through the use of CCR5 as a coreceptor.In recent years, the chemokine receptors that function as coreceptors for HIV infection have been studied extensively as potential targets for therapeutic intervention. CCR5 is very attractive because of its importance in the transmission of infection and in the evolution of disease, and a small molecule named TAK-779 inhibits the interaction between gp120 and CCR5 [194,195]. However, toxicity limits its clinical utility. More notably, an anti-CCR5 antibody, PRO 140 [196], has proven to be very effective in inhibiting infection by all R5 isolates tested [197] without inducing intracellular signaling or down-modulation of CCR5. CXCR4 has been targeted by using: (i) small cationic peptides such as ALX40-4C and T22 [198–200], that bind to the negatively charged surface of the ECL1 and ECL2 regions [201–203]; and (ii) a bicyclam compound, AMD3100 [204,205], that binds by electrostatic interaction to the region spanning the fourth transmembrane domain through the ECL2 and to the ECL3 [206]; the latter is currently in clinical trials. The potential effectiveness of these compounds within the CNS will be at least partly determined by their ability to cross the blood–brain barrier. HIV-1 infection in the CNS The presence of HIV-1 in the CNS is not a ‘passive’ or latent activity but rather represents an ‘active reservoir’ of virus, as it has been demonstrated, particularly through genotypic analyses, that viral replication takes place within the brain parenchyma [207–210]. Viral production has been also detected in autopsy tissues in the brain and during life in the CSF [211,212]. In a subset of HIV patients, infection in the CNS results in the development of symptomatology termed HIV encephalitis in children, and ADC or HAD in adults. Prior to the wide use of highly active anti-retroviral therapy (HAART), HAD developed in up to 20% of AIDS patients [213]. These patients characteristically express cognitive symptoms, including impaired short-term memory, reduced concentration, and mental slowing; manifestations of motor dysfunction such as clumsiness or slowness, tremor, and leg weakness; and behavioral symptoms including apathy, social withdrawal, irritability, depression, and personality changes [214]. More serious neurological manifestations in HIV disease typically occur in patients with high viral loads, generally when an individual has advanced systemic HIV disease or AIDS [215–218]. The principal neuropathological finding associated with HAD is the formation of multinucleated giant cells or syncytia, which are the end product of fusion between infected and uninfected cells [208,219,220]. As within the CNS HIV-1 infects mainly microglia or brain macrophages [207,208,219,220], syncytia formation is thought to be the result of fusion of microglia or brain macrophages mediated by the HIV-1 glycoproteins. Furthermore, microglia can be infected in vitro with certain HIV-1 strains [58,221–224]. As depicted in Fig. 4, microglial cells express low levels of CD4 [225,226], but also express CXCR4 and CCR5, as well as other potential HIV-1 coreceptors such as CCR3 [58,62, 227,228]." @default.
• W2324194497 created "2016-06-24" @default.
• W2324194497 creator A5049873684 @default.
• W2324194497 creator A5063594920 @default.
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• W2324194497 date "2002-09-01" @default.
• W2324194497 modified "2023-10-18" @default.
• W2324194497 title "Chemokine receptors in the brain: their role in HIV infection and pathogenesis" @default.
• W2324194497 cites W1482688899 @default.
• W2324194497 cites W1483105582 @default.
• W2324194497 cites W1487239329 @default.
• W2324194497 cites W1495127214 @default.
• W2324194497 cites W1500985028 @default.
• W2324194497 cites W150399887 @default.
• W2324194497 cites W1505517942 @default.
• W2324194497 cites W1516434930 @default.
• W2324194497 cites W1532310879 @default.
• W2324194497 cites W1558962636 @default.
• W2324194497 cites W1579558830 @default.
• W2324194497 cites W1587286994 @default.
• W2324194497 cites W1600863966 @default.
• W2324194497 cites W1607434342 @default.
• W2324194497 cites W1620558271 @default.
• W2324194497 cites W1628484047 @default.
• W2324194497 cites W1642524132 @default.
• W2324194497 cites W1643483412 @default.
• W2324194497 cites W1652900453 @default.
• W2324194497 cites W1655043483 @default.
• W2324194497 cites W1664573657 @default.
• W2324194497 cites W1669115568 @default.
• W2324194497 cites W1723922714 @default.
• W2324194497 cites W1731073298 @default.
• W2324194497 cites W1747721019 @default.
• W2324194497 cites W1765057352 @default.
• W2324194497 cites W1775940529 @default.
• W2324194497 cites W1817018401 @default.
• W2324194497 cites W1845162003 @default.
• W2324194497 cites W1846128771 @default.
• W2324194497 cites W1848605842 @default.
• W2324194497 cites W1879790343 @default.
• W2324194497 cites W1894273024 @default.
• W2324194497 cites W1904940664 @default.
• W2324194497 cites W1906710068 @default.
• W2324194497 cites W1922502842 @default.
• W2324194497 cites W1923928177 @default.
• W2324194497 cites W1963844214 @default.
• W2324194497 cites W1963855922 @default.
• W2324194497 cites W1963984954 @default.
• W2324194497 cites W1964120116 @default.
• W2324194497 cites W1965019797 @default.
• W2324194497 cites W1967014008 @default.
• W2324194497 cites W1970134919 @default.
• W2324194497 cites W1971642548 @default.
• W2324194497 cites W1971777539 @default.
• W2324194497 cites W1971833386 @default.
• W2324194497 cites W1974743648 @default.
• W2324194497 cites W1977473578 @default.
• W2324194497 cites W1978201079 @default.
• W2324194497 cites W1979568878 @default.
• W2324194497 cites W1981440980 @default.
• W2324194497 cites W1981644527 @default.
• W2324194497 cites W1981934038 @default.
• W2324194497 cites W1984115097 @default.
• W2324194497 cites W1984511547 @default.
• W2324194497 cites W1984561421 @default.
• W2324194497 cites W1986336271 @default.
• W2324194497 cites W1987547165 @default.
• W2324194497 cites W1989035987 @default.
• W2324194497 cites W1991556620 @default.
• W2324194497 cites W1993201898 @default.
• W2324194497 cites W1993387302 @default.
• W2324194497 cites W1994511844 @default.
• W2324194497 cites W1994537350 @default.
• W2324194497 cites W1995355944 @default.
• W2324194497 cites W1995504676 @default.
• W2324194497 cites W1995704105 @default.
• W2324194497 cites W1996183144 @default.
• W2324194497 cites W1998597651 @default.
• W2324194497 cites W1998757358 @default.
• W2324194497 cites W2000092232 @default.
• W2324194497 cites W2000375475 @default.
• W2324194497 cites W2001044562 @default.
• W2324194497 cites W2001486519 @default.
• W2324194497 cites W2002670780 @default.
• W2324194497 cites W2004320485 @default.
• W2324194497 cites W2005400238 @default.
• W2324194497 cites W2005780220 @default.
• W2324194497 cites W2007989611 @default.
• W2324194497 cites W2008669330 @default.
• W2324194497 cites W2009988123 @default.
• W2324194497 cites W2010521915 @default.
• W2324194497 cites W2010638326 @default.
• W2324194497 cites W2010870296 @default.
• W2324194497 cites W2011599769 @default.
• W2324194497 cites W2012547110 @default.
• W2324194497 cites W2012694713 @default.
• W2324194497 cites W2013948998 @default.
• W2324194497 cites W2016149769 @default.

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