UMLS:C0019693 - FACTA Search

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

The pivotal discovery that two chemokine receptors, CCR5 and CXCR4, serve along with the T-cell receptor-interacting CD4 molecule as the principal co-receptors for HIV-1 entry stimulated a search for common genetic polymorphism in their genes which might affect the course of AIDS. Four mutational variants, CCR5-delta32, CCR5-P1, CCR2-641 and SDF1-3'A were discovered to play a regulatory role in HIV-1 infection, in the rate of progression to AIDS or both. Plausible physiological mechanisms to explain the population genetic association by these alleles have been advanced and are discussed critically here. Genetic ablation of AIDS progression by chemokine receptor and ligand gene variants has catalyzed development of novel therapies targeting the virus-co-receptor interaction. The functional and therapeutic implications of these AIDS restriction genes for disease progression and intervention are explored in this review.
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PMID:The effect of genetic variation in chemokines and their receptors on HIV transmission and progression to AIDS. 1113 90

To ascertain whether epithelial cells of oral cavity origin may be infected with human immunodeficiency virus (HIV-1), a study to determine susceptibility to infection of salivary gland epithelial cell lines (HSY and HSG) was undertaken. Because of the potential for oral-genital transmission, an endometrial cell line, HEC-1, was also studied. Epithelial cell monolayers were infected with cell-free HTLVIIIB or a primary HIV-1 isolate. Several lines of evidence indicated that inoculation of these cell lines with HIV-1 led to productive infection: 1) p24 antigen was present in supernatants, with levels peaking on days 3-4; 2) provirus was found in cells by polymerase chain reaction; 3) virions present in supernatants were infectious as confirmed by coculture with the T-lymphoblastoid line CEM-NKr. Following a period of virus production, HIV-1 entered a latency phase over 10 weeks. All epithelial cell lines were positive for galactosylceramide (GalC) and CXCR4. HSY was weakly positive for surface CD4, and also expressed mRNA for CD4 and CCR5, as did HEC-1. Blocking studies indicated that anti-GalC, but not anti-CD4, significantly reduced productive infection, and that regulated on activation normal T cell expressed and secreted (RANTES) but not stromal cell-derived factor (SDF-1) could partially block infection of the M-tropic primary isolate. These results suggest that epithelial cells in the oral cavity and the genital tract might be targets of HIV-1 and potentially serve as a mediator of systemic infection.
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PMID:Productive human immunodeficiency virus-1 infection of epithelial cell lines of salivary gland origin. 1115 70

Chemokine receptors (CCR5, CXCR4 and CCR2) have been shown to be important co-receptors for HIV infection. Mutations at CCR5 (CCR5-delta2), CCR2 (CCR2-641), and stromal-derived factor SDF1 (SDF1-3'A), a primary ligand for CXCR4, are known to have protective effects against HIV-1 infection and the onset of AIDS symptoms. We studied the three-locus genotype frequency distributions in 70worldwide populations from a sample of 2341 individuals without any known history of HIV-1 infection and AIDS symptoms. From these data, we estimated the risk of AIDS onset (relative hazard, RH) of each population. This survey shows that the substantial allele frequency differences of each of these mutations translate into an extensive variation in relative hazards for AIDS in worldwide populations. However, no evidence of natural selection against the mutant gene carriers is detected. Finally, the combined three-locus genotype data predict the highest relative hazard (RH) in South-East Asia and Africa where AIDS is known to be more prevalent.
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PMID:Distribution of three HIV-1 resistance-conferring polymorphisms (SDF1-3'A, CCR2-641, and CCR5-delta32) in global populations. 1117 86

The CXC chemokine stromal cell-derived factor (SDF)-1 is produced constitutively in different tissues. It is the only known ligand for CXCR4, which is widely expressed in leukocytes and in some tissue cells, and acts as coreceptor for X4 HIV strains. Because of the general interest in the mechanisms that regulate the activity of constitutively expressed chemokines, we have studied the inactivation of SDF-1 in cells that bear CXCR4. Here we show that B lymphocytes, NK cells and, to a lesser extent, T lymphocytes inactivate SDF-1 by N-terminal processing. Inactivation is due to cathepsin G which is associated with the membrane of lymphocytes and rapidly cleaves off five N-terminal residues by acting on the Leu(5)-Ser(6) bond yielding SDF-1(6-67). Processing was observed with intact cells, cell membrane preparations and soluble cathepsin G obtained by extraction of the membranes with Triton X-100. Cathepsin G is released by neutrophils and monocytes and binds on the surface of lymphocytes by an apparently saturable process. Analysis of the product obtained, the time course and the sensitivity to inhibitors shows that cathepsin G is the only protease involved. Conversion of SDF-1 to SDF-1(6-67) was complete within minutes to 1-2 h depending on the enzyme source, and was abrogated by inhibitors of serine proteases and chymostatin. Diprotin A, an inhibitor of dipeptidyl peptidase IV, was without effect. Owing to its availability on the surface of SDF-1-responsive cells and its rapid effect, cathepsin G is likely to play a significant role in down-regulating SDF-1 activity.
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PMID:Rapid inactivation of stromal cell-derived factor-1 by cathepsin G associated with lymphocytes. 1124 Dec 73

Host factors such as increased beta-chemokine production, HIV-1 coreceptor expression level, and HIV-1 coreceptor polymorphism have been thought to influence susceptibility to HIV-1 infection. To determine the protective role of these factors in Ethiopians who remained HIV-1 uninfected, despite multiple high-risk sexual exposures, we studied 21 Ethiopian women who had been employed as commercial sex workers (CSWs) for five or more years. The HIV-1-resistant CSWs were compared with low-risk age-matched female controls who had a comparable CD4+ cell percentage and mean fluorescence intensity (MFI). Genetic polymorphism in the CCR5, CCR2b, or SDF-1 genes appeared not to be associated with resistance in the Ethiopian CSWs. Expression levels of CCR5 and CXCR4 on naive, memory, and total CD4+ T cells tended to be higher in the resistant CSWs, while the production of beta-chemokines RANTES, MIP-1alpha, and MIP-1beta by phytohemagglutinin (PHA)-stimulated peripheral blood mononuclear cells (PBMCs) was lower compared with low-risk HIV-1 negative controls. In vitro susceptibility of PHA-stimulated PBMCs to primary, CCR5-restricted, Ethiopian HIV-1 isolates was comparable between resistant CSWs and low-risk controls. In vitro susceptibility was positively correlated to CD4+ cell mean fluorescence intensity and negatively correlated to CCR5 expression levels, suggesting that infection of PBMCs was primarily dependent on expression levels of CD4 and that CCR5 expression, above a certain threshold, did not further increase susceptibility. Our results show that coreceptor polymorphism, coreceptor expression levels, beta-chemokine production, and cellular resistance to in vitro HIV-1 infection are not associated with protection in high-risk HIV-1-negative Ethiopian CSWs.
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PMID:No difference in in vitro susceptibility to HIV type 1 between high-risk HIV-negative Ethiopian commercial sex workers and low-risk control subjects. 1128 12

Interaction between the human immunodeficiency virus type 1 (HIV-1) envelope and the relevant chemokine receptors is crucial for subsequent membrane fusion and viral entry. Although the V3 region of gp120 is known to determine the cell tropism as well as the coreceptor usage, the significance of the binding of the V3 region to the chemokine receptor has not been fully understood. To address this issue, we adopted the pseudotyped virus infection assay in which the V3 region of the T-cell line-tropic (T-tropic) NL4-3 envelope was replaced with a portion of stromal cell-derived factor 1 (SDF-1), the ligand of CXCR4. The V3 region of the NL4-3 envelope expression vector was replaced with three different stretches of SDF-1 cDNA. Expression of each chimeric envelope protein was confirmed by immunoprecipitation and Western blotting. Luciferase reporter viruses were prepared by cotransfection of the pNL4-3.Luc.E(-)R(-) vector and each chimeric envelope expression vector, and the infection assay was then carried out. We showed that pseudotyped viruses with one of the chimeric envelopes, NL4-3/SDF1-51, could infect U87.CD4.CXCR4 but not U87.CD4 or U87.CXCR4 cells and that this infection was inhibited by the ligand of CXCR4, SDF-1beta, by anti-human SDF-1 antibody, or by an anti-CD4 antibody, Leu3a, in a dose-dependent manner. Furthermore, chimeric NL4-3/SDF1-51 gp120 significantly inhibited binding of labeled SDF-1 to CXCR4. It was suggested that replacement of the V3 region of the NL4-3 envelope with SDF-1 preserved the CD4-dependent infectivity of T-tropic HIV-1. These results indicate that binding between the V3 region and the relevant coreceptor is important for viral entry, whether its amino acid sequence is indigenous to the virus or not.
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PMID:Replacement of the V3 region of gp120 with SDF-1 preserves the infectivity of T-cell line-tropic human immunodeficiency virus type 1. 1128 75

The CCR5 Delta32, CCR2 64I, SDF1 3'A, and CCR5 promoter 59029 polymorphisms have been suggested to influence HIV-1 disease progression. Furthermore, the CCR5 Delta32 and the CCR2 64I polymorphisms have been associated with various other diseases. The purpose of the present study was to develop a multiplex assay for the simultaneous determination of these four polymorphisms. Results obtained with the multiplex assay were compared to results obtained by conventional RFLP-PCR and no differences were observed. The multiplex assay offers a quick tool for the determination of the CCR5 Delta32, CCR2 64I, SDF1 3'A, and CCR5 promoter 59029 A/G polymorphisms.
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PMID:A new multiplex PCR strategy for the simultaneous determination of four genetic polymorphisms affecting HIV-1 disease progression. 1133 74

The chemokine receptors CXCR4 and CCR5 are considered to be potential targets for the inhibition of HIV-1 replication. We have reported that T134 and T140 inhibited X4 HIV-1 infection specifically because they acted as CXCR4 antagonists. In the present study, we have generated a T134-resistant virus (trHIV-1(NL4-3)) in a cell culture with gradually increasing concentrations of the compound. The EC(50) of T134 against trHIV-1(NL4-3) recovered after 145 passages was 15 times greater than that against wild-type HIV-1(NL4-3). This adapted virus was resistant to other CXCR4 antagonists, T140, AMD3100, and ALX40-4C, and SDF-1; from 10 to 145 times greater than that against wild-type HIV-1(NL4-3). On the other hand, T134, T140, and ALX40-4C were still active against AMD3100-resistant viruses (arHIV-1(018A)). The trHIV-1(NL4-3) contained the following mutations in the V3 loop of gp120: N269K, Q278T, R279K, A284V, F285L, V286Y, I288T, K290E, N293D, M294I, and Q296K; an insertion of T at 290; and Delta274-275 (SI). In addition, many other mutations were recognized in the V1, V2, and V4 domains. Thus, resistance to T134 may be the consequence of amino acid substitutions in the envelope glycoprotein of X4 HIV-1. The trHIV-1(NL4-3) could not utilize CCR5 as an HIV infection coreceptor, although many amino acid substitutions were recognized. The trHIV-1(NL4-3) acquired resistance to vMIP II, which could inhibit both X4 and R5 HIV-1 infection. However, neither the ligands of CCR5, RANTES, and MIP-1alpha, nor a CCR5 low molecular antagonist, TAK-779, were able to influence the infection of trHIV-1(NL4-3). Those results indicated that alternation of coreceptor usage of trHIV-1(NL4-3) was not induced.
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PMID:Biological and genetic characterization of a human immunodeficiency virus strain resistant to CXCR4 antagonist T134. 1137 57

The chemokine receptors CXCR4 and CCR5 are considered to be potential targets for the inhibition of HIV-1 replication. We found that the synthetic peptides T134 and T140 (see text for full names) inhibited X4 HIV-1 infection with selectivity and low toxicity because they acted as CXCR4 antagonists. However, high concentrations of T134, T140, and ALX40-4C (see text for full name) increased the expression of CCR5 and R5 HIV-1 infection, as did stromal cell-derived factor 1 (SDF-1). In contrast to CXCR4 antagonists and SDF-1, viral monocyte inflammatory protein (vMIP) II inhibited not only anti-CXCR4 monoclonal antibody (MAb) but also inhibited anti-CCR5 MAb binding to human peripheral blood mononuclear cells, and inhibited both X4 and R5 HIV-1 strains. T134, T140, ALX40-4C, and SDF-1 increased viral transcription in the treated cells. In addition, ALX40-4C and SDF-1 also increased nuclear transcription factor (NF)-kappaB. However, the mechanisms of action of T134 and T140 are different from those of clinically used anti-HIV drugs. Thus, synergistic activities were observed in the concomitant treatment with T134 and reverse transcriptase inhibitors or protease inhibitors. Our findings, presented here, are noteworthy in regard to the potential clinical use of these agents as drugs for the treatment of AIDS.
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PMID:Increase of R5 HIV-1 infection and CCR5 expression in T cells treated with high concentrations of CXCR4 antagonists and SDF-1. 1140 54

Astrocytes actively participate in synaptic integration by releasing transmitter (glutamate) via a calcium-regulated, exocytosis-like process. Here we show that this process follows activation of the receptor CXCR4 by the chemokine stromal cell-derived factor 1 (SDF-1). An extraordinary feature of the ensuing signaling cascade is the rapid extracellular release of tumor necrosis factor-alpha (TNFalpha). Autocrine/paracrine TNFalpha-dependent signaling leading to prostaglandin (PG) formation not only controls glutamate release and astrocyte communication, but also causes their derangement when activated microglia cooperate to dramatically enhance release of the cytokine in response to CXCR4 stimulation. We demonstrate that altered glial communication has direct neuropathological consequences and that agents interfering with CXCR4-dependent astrocyte-microglia signaling prevent neuronal apoptosis induced by the HIV-1 coat glycoprotein, gp120IIIB. Our results identify a new pathway for glia-glia and glia-neuron communication that is relevant to both normal brain function and neurodegenerative diseases.
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PMID:CXCR4-activated astrocyte glutamate release via TNFalpha: amplification by microglia triggers neurotoxicity. 1142 15

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