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Query: UMLS:C0019693 (HIV)
 170,526 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

CC chemokine receptor 5 (CCR5) is a cell entry cofactor for macrophage-tropic isolates of human immunodeficiency virus 1 (HIV-1). An inactive CCR5 allele with a 32-nucleotide deletion (CCR5Delta32) has been described that confers resistance to HIV-1 infection in homozygotes and slows the rate of progression to AIDS in heterozygotes. We found the allele CCR5Delta32 to be not rare in 399 Swiss blood donors with a frequency of 0.080. To assess the influence of defective CCR5 on production of its ligands we determined the capacity to produce the chemokines macrophage inflammatory protein (MIP)-1alpha, MIP-1beta and RANTES in comparison with the production of the CXC chemokine IL-8 which does not bind to CCR5. Production of chemokines was determined during endotoxin stimulation of whole-blood samples ex vivo. Both, basal and LPS-induced chemokine production in 32 blood donors heterozygous for CCR5Delta32 were not significantly different when compared with 55 blood donors who were homozygous for the wild type CCR5 allele.
Cytokine 1999 Jan
PMID:Heterozygous defect in HIV-1 coreceptor CCR5 and chemokine production. 1008 Aug 73

Recent evidence indicates that the rate of progression of the HIV-1 disease is significantly reduced in thalassaemia major patients upon treatment with high doses of desferrioxamine (DFX). The authors have previously demonstrated that in vitro exposure of mononuclear cells to DFX decreases the bioavailability of tumour necrosis factor alpha (TNF-alpha) which has a stimulatory effect on HIV-1 replication. In this study, therefore, TNF-alpha bioavailability from mononuclear cells isolated from 10 patients with thalassaemia or sickle cell anaemia given DFX as compared to 10 untreated subjects has been evaluated. Evidence is presented showing that DFX treatment reduces TNF-alpha bioavailability (P<0.05) by inhibiting its steady state (P<0.05) and by enhancing its inactivation through binding to soluble TNF-alpha receptor type II (P<0.05). We also show that DFX treatment limits the in vivo activation of NF-kappaB, a transcription factor involved in both TNF-alpha gene transcription and TNF-alpha signalling (P<0.005). We conclude that TNF-alpha bioavailability and signalling are impaired in patients upon DFX treatment. This mechanism may contribute to delayed progression of the HIV-1 infection in vivo.
Cytokine 1999 Feb
PMID:Reduction of tumour necrosis factor alpha expression and signalling in peripheral blood mononuclear cells from patients with thalassaemia or sickle cell anaemia upon treatment with desferrioxamine. 1008 40

To assess DNA immunization as a strategy for protecting against HIV infection in humans, we utilized SIVmne infection of Macaca fascicularis as a vaccine challenge model with moderate pathogenic potential. We compared the efficacy of DNA immunization alone and in combination with subunit protein boosts. All of the structural and regulatory genes of SIVmne clone 8 were cloned into mammalian expression vectors under the control of the CMV IE-1 promoter. Eight M. fascicularis were immunized twice with 3 mg of plasmid DNA divided between two sites; intramuscular and intradermal. Four primed macaques received a further two DNA immunizations at weeks 16-36, while the second group of four were boosted with 250 microg recombinant gp160 plus 250 microg recombinant Gag-Pol particles formulated in MF-59 adjuvant. Half of the controls received four immunizations of vector DNA; half received two vector DNA and two adjuvant immunizations. As expected, humoral immune responses were stronger in the macaques receiving subunit boosts, but responses were sustained in both groups. Significant neutralizing antibody titers to SIVmne were detected in one of the subunit-boosted animals and in none of the DNA-only animals prior to challenge. T-cell proliferative responses to gp160 and to Gag were detected in all immunized animals after three immunizations, and these responses increased after four immunizations. Cytokine profiles in PHA-stimulated PBMC taken on the day of challenge showed trends toward Thl responses in 2/4 macaques in the DNA vaccinated group and in 1/4 of the DNA plus subunit vaccinated macaques; Th2 responses in 3/4 DNA plus subunit-immunized macaques; and Th0 responses in 4/4 controls. In bulk CTL culture, SIV specific lysis was low or undetectable, even after four immunizations. However, stable SIV Gag-Pol- and env-specific T-cell clones (CD3+ CD8+) were isolated after only two DNA immunizations, and Gag-Pol- and Nef-specific CTL lines were isolated on the day of challenge. All animals were challenged at week 38 with SIVmne uncloned stock by the intrarectal route. Based on antibody anamnestic responses (western, ELISA, and neutralizing antibodies) and virus detection methods (co-culture of PBMC and LNMC, nested set PCR- of DNA from PBMC and LNMC, and plasma QC-PCR), there were major differences between the groups in the challenge outcome. Surprisingly, sustained low virus loads were observed only in the DNA group, suggesting that four immunizations with DNA only elicited more effective immune responses than two DNA primes combined with two protein boosts. Multigenic DNA vaccines such as these, bearing all structural and regulatory genes, show significant promise and may be a safe alternative to live-attenuated vaccines.
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PMID:Protection from pathogenic SIV challenge using multigenic DNA vaccines. 1020 53

The broad range of histological lesions associated with HIV-1 are somewhat subtle relative to the clinical manifestations that occur as a result of HIV infection. Although it is clear that HIV has a causative role in CNS disease, dementia appears to be a consequence of the infiltration of inflammatory cells and cytokine dysregulation rather than the amount of virus in CNS. The HIV transregulatory protein Tat plays an important intracellular as well as extracellular role in the dysregulation of cytokines. The cytokines and possibly chemokines that are induced by Tat modify the action of astrocytes such that the survival of neurons is compromised. Pathogenetic alteration induced by Tat involves a series of interactions between circulating monocyte/macrophages, endothelial cells, and astrocytes. Cytokine dysregulation induced by viral infection and extracellular Tat leads to alterations in expression of adhesion molecules and promotes migration of non-infected inflammatory cells into the CNS compartment. We demonstrate here that recombinant HIV-1 Tat protein introduced by stereotaxic injection into mouse brain can induce pathologically relevant alterations including macrophage invasion as well as astrocytosis. The mechanism of destruction of the CNS by Tat appears to involve autocrine and paracrine pathways that depend not only on Tat, but cytokine and chemokine signaling pathways that are altered by viral infection. In this review, we discuss various pathogenic effects of Tat in brain cells and provide experimental evidence for an increased TNF-alpha level in CSF in mice injected intracerebrally with Tat protein.
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PMID:Molecular pathway involved in HIV-1-induced CNS pathology: role of viral regulatory protein, Tat. 1020 74

We wished to determine the effects of the beta-chemokine RANTES in an established system of cell-mediated transmission of HIV-1, that is, normal human umbilical vein endothelial cells (HUVEC) nonproductively infected with HIV-1, cocultivated with CD4+ T cells to rescue productive infection. The results indicate that the addition of RANTES to HUVEC, either before or after HIV-1 infection, stimulates HIV-1 rescue by CD4+ T cells. However, viral DNA is not increased in HUVEC, suggesting that the stimulation exerted by RANTES could be mediated by events following HUVEC infection. The mechanisms of increase seem to be related to the rescue phase, involving membrane interaction of abortively infected HUVEC with permissive T cells. In fact, a strong upregulation and polarization of intercellular adhesion molecule-1 (ICAM-1) is induced in HUVEC by RANTES, and antibodies against ICAM-1 inhibit HIV-1 rescue by T cells. These results indicate that RANTES, similarly to other inflammatory cytokines, may favor HIV-1 spreading and crossing of blood-tissue barriers by indirect mechanisms involving membrane interactions between nonproductively infected and permissive cells.
J Interferon Cytokine Res 1999 Apr
PMID:RANTES stimulates cell-mediated transmission of HIV-1 infection. 1033 85

Migration of leukocytes from the bone marrow to the circulation, the primary lymphoid organs and inflammatory sites is directed by chemokines and specific receptor interactions. Besides the role of this group of low molecular weight cytokines in leukocyte attraction and activation, anti-HIV and hematopoietic activities were also attributed to chemokines. On the basis of the number and arrangement of the conserved cysteines, chemokines are subdivided in two multi-member families, namely the CXC and CC chemokines, whereas fractalkine (CX3C) and lymphotactin (C) are unique relatives. The CC chemokines possess four cysteines of which the first two are adjacent. Functionally, they form a rather heterogeneous family. Here, the focus is on the monocyte chemotactic proteins and eotaxin which, on a structural basis, can be considered as a CC chemokine subfamily. Not only the protein sequences, but also the gene structures, chromosomal location, biological activities and receptor usage exhibit considerable similarities. The review is complemented with a comparison of the biological functions of the MCP/eotaxin-subfamily in physiology and pathology.
Cytokine Growth Factor Rev 1999 Mar
PMID:The MCP/eotaxin subfamily of CC chemokines. 1037 12

Vertical transmission of HIV-1 can occur at three different stages: during gestation, delivery and breast feeding. To determine the role of cytokines in vertical transmission of HIV during gestation, we studied the secretion of IL-1beta, TNF-alpha and IL-6 from in vitro infected and Mock-infected placental macrophages (Hofbauer cells) in comparison to blood monocyte derived macrophages (MDM). Hofbauer cells stimulated with lipopolysaccharide (LPS) secreted lower levels of HIV stimulatory cytokines (6-8 ng/ml) in the supernatants than MDM (26 ng/ml, p<0.005). Cytokine levels in MDM decreased upon HIV infection to 7 ng/ml. IL-6 was the major cytokine produced after LPS stimulation by the two cell populations (p<0.005), being MDM the major cytokine producer. In vitro infection studies with a M-tropic virus (HIV-BaL) indicated that MDM were 10x more susceptible to HIV than placental macrophages (p=0.001). Our results indicate that although macrophages from term placenta secrete lower amount of HIV stimulatory cytokines than MDM, there was no correlation between the levels of cytokines and HIV production by both cells.
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PMID:HIV infection of placental macrophages: effect on the secretion of HIV stimulatory cytokines. 1043 89

Our objective was to study the influence of HIV infection of polymorphonuclear leukocytes (PMN) on transepithelial migration. To date, reports of functional PMN chemotaxis in AIDS are contradictory. This is the first attempt to assess this function via an in vitro model allowing transmigration of neutrophils through an intestinal epithelial barrier. PMN were isolated from 45 HIV-infected patients and 45 healthy volunteers. PMN transmigration across T84 epithelial cells was initiated by applying either various concentrations of formyl-met-leu-phe peptide (f-MLP) or interleukin-8 and assayed by quantification of myeloperoxidase activity. CD11b, CD18, and CD47 expression on PMN was compared before and after transepithelial migration by flow cytometry analysis. CD11b expression was studied by electron microscopy. Apoptosis of transmigrated HIV PMN and control PMN was investigated by morphology and DNA fragmentation characterization. Compared to control PMN, HIV PMN exhibited a decrease in transepithelial migration that directly correlated with CD4+ counts. Basal and transepithelial migration-mediated expression of CD11b, CD18, and CD47 were unmodified in HIV PMN compared to control PMN. Electron microscopy labeling confirmed no difference in CD11b expression on HIV and control PMN. The index of apoptosis in transmigrated HIV PMN and control PMN was identical. These data provide evidence of a defect in the f-MLP-induced chemotaxis of PMN from HIV-infected patients across an intestinal epithelial barrier. This defective migration is not due to a quantitative modification of CD11b, CD18 and CD47 on HIV PMN suggesting a more subtle alteration. The impairment in the transmigration function may contribute in vivo to an increased susceptibility to intestinal bacterial infection in HIV-infected patients.
Eur Cytokine Netw 1999 Sep
PMID:Impairment of HIV polymorphonuclear leukocyte transmigration across T84 cell monolayers: an alternative mechanisms for increased intestinal bacterial infections in AIDS? 1047 94

Cytokine dysregulation is accepted as one of the pivotal factors in the pathogenesis of B cell lymphomas in HIV-positive patients. So far no data exist on inhibitory cytokines in the regulatory network of HIV-associated B-NHL. Simian immunodeficiency virus (SIV)-infected macaques are a well-established in vivo model of HIV infection in humans. We used this model for the identification of TGF-beta as a growth-inhibitory cytokine of SIV-associated B cell lymphomas. Fifty-seven rhesus macaques were infected with SIVmac. Nine animals developed B cell lymphomas: eight with high-grade lymphomas of the immunoblastic, centroblastic, and "Burkitt-like" type, and one with the centroblastic/centrocytic type according to the Kiel classification. Six of seven analyzed lymphomas were infected with the macaque EBV, herpes virus macaca mulatta (HVMM). The lymphomas and the SIV-associated B cell lymphoma cell line H50 were positive for transcription of the TGF-beta gene. Protein expression and secretion of the active cytokine were proved by immunohistochemistry and ELISA. H50 transcribed the TGF-beta type I and type II receptor (R I/II), betaglycan, and endoglin. Furthermore, all primary lymphoma samples tested were positive for receptor type I/II transcription and protein expression. TGF-beta induced reduction of cell viability by 67% (range, 50-84% and enhanced apoptosis by 69% (range, 33-111%) compared with the control. TGF-beta activity was blocked by a specific anti-TGF-beta antibody. Thus, TGF-beta fulfilled the criteria of a negative autocrine inhibitor in H50. These data identify TGF-beta as a promising candidate as an inhibitory factor in the regulatory network of HIV-associated lymphomagenesis.
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PMID:Transforming growth factor beta is a growth-inhibitory cytokine of B cell lymphoma in SIV-infected macaques. 1055 11

Over the past decade, the involvement of tyrosine kinases in signal transduction pathways evoked by cytokines has been intensively investigated. Only relatively recently have the roles of serine/threonine kinases in cytokine-induced signal transduction and anti-apoptotic pathways been examined. Cytokine receptors without intrinsic kinase activity such as interleukin-3 (IL-3), granulocyte-macrophage colony-stimulating factor (GM-CSF) and the interferons were thought to transmit their regulatory signals primarily by the receptor-associated Jak family of tyrosine kinases. This family of tyrosine kinases activates STAT transcription factors, which subsequently transduced their signals into the nucleus to modulate gene expression. Cytokine receptors with intrinsic tyrosine kinase activity such as c-Kit were initially thought to transduce their signals independently of serine/threonine kinase cascades. Recently, both of these types of receptor signaling pathways have been shown to interact with serine/threonine kinase pathways as maximal activation of these tyrosine kinase regulated cascades involve serine/threonine phosphorylation modulated by, for example MAP kinases. A common intermediate pathway initiating from cytokine receptors is the Ras/Raf/MEK/ERK (MAPK) cascade, which can result in the phosphorylation and activation of additional downstream kinases and transcription factors such as p90Rsk, CREB, Elk and Egr-1. Serine/threonine phosphorylation is also involved in the regulation of the apoptosis-controlling Bcl-2 protein, as certain phosphorylation events induced by cytokines such as IL-3 are anti-apoptotic, whereas other phosphorylation events triggered by chemotherapeutic drugs such as Paclitaxel are associated with cell death. Serine/threonine phosphorylation is implicated in the etiology of certain human cancers as constitutive serine phosphorylation of STATs 1 and 3 is observed in chronic lymphocytic leukemia and can be inhibited by the chemotherapeutic drug fludarabine. Serine/threonine phosphorylation also plays a role in the etiology of immunodeficiencies. Activated STAT5 proteins are detected in reduced levels in lymphocytes recovered from HIV-infected individuals and immunocompromised mice. Serine/threonine phosphorylation may be an important target of certain chemotherapeutic drugs which recognize the activated proteins. This meeting report and mini-review will discuss the interactions of serine/threonine kinases with signal transduction and apoptotic molecules and how some of these pathways can be controlled by chemotherapeutic drugs. Leukemia (2000) 14, 9-21.
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PMID:Serine/threonine phosphorylation in cytokine signal transduction. 1063 71


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