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)

Uni- or multi-lineage suppression of hematopoiesis is observed in the majority of acquired immunodeficiency syndrome (AIDS) patients. The mechanism(s) underlying these abnormalities is not understood: particularly, the human immunodeficiency virus (HIV) infection of hematopoietic progenitor and stem cells (HPCs/HSCs) is highly controversial. We report that CD34+ HPCs from adult peripheral blood (PB) are in part CD4+ and susceptible to in vitro HIV infection. Primitive CD34+ HPCs were approximately 80% purified from PB. Double labeling for CD34 and CD4 membrane antigens was shown for 5% to 20% of the purified cells, thus suggesting their potential susceptibility to HIV-1 infection. The enriched HPC population, challenged with purified or unpurified HIV-1 strains, was cloned in unicellular methylcellulose culture. The single colonies generated by erythroid burst-forming units (BFU-E), granulocyte-macrophage colony-forming units (CFU-GM), and granulocyte-erythroid-macrophage-megakaryocyte colony-forming units (CFU-GEMM) were analyzed for the presence of HIV, ie, for gag DNA, tat mRNA, and p24 protein by PCR, reverse transcription PCR (RT-PCR), and enzyme-linked immunosorbent assay, respectively. In the first series of experiments incubation of HPCs with HIV-1 at multiplicities of infection (MOI) ranging from 0.01 to 10 TCID50/cell consistently yielded an 11% to 17% infection efficiency of BFU-E-generated colonies, thus indicating the sensitivity of HPCs to in vitro HIV infection. An extensive series of experiments was then performed on HPCs challenged with HIV at 0.1 MOI level. In the initial studies proviral gag sequences were detected in 9.2% of 121 analyzed CFU-GM colonies. In further experiments tat mRNA was monitored in 17% and 23% of BFU-E and CFU-GM colonies, respectively, but never in CFU-GEMM clones. Finally, 12% of CFU-GM clones and rare erythroid bursts were shown to be positive for the p24 viral protein. In control studies, purified HPCs grown in liquid suspension culture were induced to terminal unilineage erythroid, monocytic, or granulocytic differentiation: monocytes were consistently HIV-infected, whereas mature-terminal erythroblasts and granulocytes were not. Our observations indicate that a minority of primitive HPCs, but not of the multipotent type, is susceptible to in vitro HIV infection. These observations may reflect on the in vivo hematopoietic impairment in AIDS patients; more important, they provide an experimental model for studies on HIV hematopoietic infection and in vitro tests for anti-HIV HSC gene therapy.
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PMID:In vitro human immunodeficiency virus-1 infection of purified hematopoietic progenitors in single-cell culture. 753 32

Controversy exists as to whether hematopoietic progenitor cells are infected by human immunodeficiency virus-1 (HIV-1) in vivo. Most studies have focused on patients with acquired immunodeficiency syndrome (AIDS)/AIDS-related complex, and little data are available on asymptomatic patients with well preserved CD4+ T-cell counts. To determine if CD34+ hematopoietic progenitor cells are infected early in the course of HIV-1 disease, we evaluated 10 asymptomatic HIV-1 seropositive (HIV-1+) patients. The CD34+ cell fraction was purified by a two-step procedure consisting of both affinity chromatography and fluorescence-activated cell sorting that resulted in a median purity of over 99%. Using conventional and nested polymerase chain reaction (PCR) assays, we evaluated the presence and frequency of HIV-1 proviral DNA. Both bone marrow mononuclear cells and CD34- cells from all 10 patients were strongly positive for the HIV-1 pol and/or gag gene sequences. In contrast, sorted CD34+ cells from only two of 10 patients were positive, and the number of copies of proviral DNA in these samples was estimated to be from 2 to 5 per 250,000 cells. To test the in vitro functional capacity of CD34+ progenitors, these cells were assayed in both methylcellulose and long-term stromal culture. We found no significant reduction in the number of colony-forming unit-erythroid (CFU-E), burst-forming unit-erythroid (BFU-E), or colony-forming unit-granulocyte macrophage (CFU-GM) colonies, or in the frequency of cobblestone area forming cells from limit dilution analysis in HIV-1+ asymptomatic patients. Pooled methylcellulose colonies generated from CD34+ cells were HIV-1- in nine of 10 samples. All progeny from long-term cultures of CD34+ cells were HIV-1-. We conclude that the CD34+ hematopoietic progenitor compartment is not infected in the majority of asymptomatic HIV-1+ patients, and that these cells may represent a suitable target for strategies designed to protect developing CD4+ T cells from infection.
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PMID:CD34+ progenitor cells from asymptomatic patients are not a major reservoir for human immunodeficiency virus-1. 754 40

Dendritic cells have been isolated from the epidermis, dermis, and lymphatics of skin. Cells from each cutaneous compartment can exhibit the distinct morphology, surface phenotype, and strong T-cell-stimulating activity of dendritic cells that are isolated from other organs. Of importance are the mechanisms by which the maturation and movement of dendritic cells are regulated within intact tissues. Epidermal dendritic cells turn over slowly in the steady state. Stimuli, including contact allergens and transplantation, perhaps by inducing a release of cytokines such as granulocyte macrophage-colony-stimulating factor, mobilize these dendritic cells into the dermis and lymph. This migration is accompanied by the maturation of dendritic cell functions; e.g., antigen-presenting major histocompatibility complex molecules and B7 costimulators increase markedly. On the other hand, there is a sizable, steady-state flux of dendritic cells in afferent lymph draining the skin, which suggests a constant traffic through the dermis that is independent of sessile epidermal dendritic cells. When explants of skin are placed in organ culture, dendritic cells emigrate into the medium for 1-3 d. The dendritic cells are mature and can bind tightly to small memory T cells that also migrate in these cultures. The emigrated mixtures of dendritic cells and T cells should be useful in the study of many clinical states. This is illustrated by recent experiments showing that migratory skin cells are readily infected with human immunodeficiency virus (HIV)-1. A strong productive infection takes place in the absence of exogenous cytokines, foreign sera, or mitogens or antigens. The dendritic cell-T-cell conjugates are the essential site for infection. This cellular milieu may model events during the sexual transmission of HIV-1, where relevant mucosal surfaces are covered by skin-like epithelia. The capture of CD4+ memory T cells by dendritic cells may explain the chronic drain of immune memory in HIV infection.
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PMID:Maturation and migration of cutaneous dendritic cells. 761 92

Activation of CD4 positive T cells is a primary requirement for human immunodeficiency virus (HIV) entry, efficient HIV replication, and progression to AIDS, Utilizing CD4 positive T cell lines and purified T cells from normal individuals, we have demonstrated that native envelope glycoproteins of HIV, gp 160, can induce activation of transcription factor, activated protein-1 (AP-1). The stimulatory effects of gp160 are mediated through the CD4 molecule, since treatment of gp160 with soluble CD4-IgG abrogates its activity, and CD4 negative T cell lines fail to be stimulated with gp160. Immunoprecipitation of the gp 160-induced nuclear extracts with polyclonal antibodies to Fos and Jun proteins indicates that AP-1 complex is comprised of members of these family of proteins. The gp160-induced AP-1 complex is dependent upon protein tyrosine phosphorylation and is protein synthesis-independent. This stimulation can also be abolished by inhibitors of protein kinase C, but it is unaffected by calcium channel blocker or cyclosporine A. This gp160 treatment adversely affects the functional capabilities of T cells: pre-treatment of CD4+ T cells with gp160 for 4 h at 37 degrees C inhibited anti-CD3-induced interleukin-2 secretion. Effects similar to gp160 were seen with anti-CD4 mAb. The aberrant activation of AP-1 by gp160 in CD4 positive T cells could result in up-regulation of cytokines containing AP-1 sites, e.g. interleukin-3 and granulocyte macrophage colony-stimulating factor, and concurrently lead to T cell unresponsiveness by inhibiting interleukin-2 secretion.
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PMID:HIV-1 envelope glycoproteins induce activation of activated protein-1 in CD4+ T cells. 764 15

In this paper we investigated the role played by human immunodeficiency virus type 1 (HIV-1) in the pathogenesis of peripheral blood (PB) cytopenias of AIDS patients. The in vitro growth of PB granulocyte/macrophage progenitors (CFU-GM) was investigated in 45 HIV-1 seropositive (+) individuals at different stages of the disease. The number of circulating CFU-GM was significantly (p < 0.01) lower in AIDS patients (stages WR V-VI) than in HIV-1(+) asymptomatic individuals (stages WR I-II). Moreover, the presence of gag p 24 in the plasma and/or viral isolation from PB mononuclear cells of HIV-1(+) individuals was inversely correlated (p < 0.01) with the number of circulating CFU-GM, irrespectively with the stage of the disease. Viral isolates obtained from one asymptomatic and four symptomatic HIV-1(+) individuals were tested on the in vitro growth of normal hematopoietic progenitor (CD34+) cells, purified from PB of healthy donors. All the different viral isolates showed a dose-dependent inhibition of CD34+ cells, in the absence of either productive or latent infection. This suppressive effect was completely reversed by preincubating the different viral isolates with a polyclonal anti-gp 120 antibody before adding to normal CD34+ cells. These findings suggest a direct involvement of active viral replication products in the progressive impairment of hematopoiesis, characteristic of HIV-1(+) individuals in spite of the lack of a productive or latent infection of CD34+ hematopoietic progenitors.
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PMID:The impaired number of circulating granulocyte/macrophage progenitors (CFU-GM) in human immunodeficiency virus-type 1 infected subjects correlates with an active HIV-1 replication. 768 5

Hematologic abnormalities in the peripheral blood and bone marrow are associated with human immunodeficiency and simian immunodeficiency virus (HIV, SIV) infection. The reasons for these abnormalities remain unclear. Bone marrow specimens collected from uninfected animals (Group A, Controls) and from rhesus macaques experimentally infected with SIVsmm9 during the asymptomatic stage (Group B, SIV+ "well") and during the clinically ill stage (Group C, SIV+ "sick"), underwent a variety of in vitro assays of hematopoiesis. Colony forming unit-granulocyte/macrophage (CFU-GM) per plate growth was 46.7 +/- 7.7, 31.9 +/- 8.4 and 6.5 +/- 5.0 (mean +/- sd, P < .02 each mean compared to the others) in the 3 groups respectively. Burst forming unit-erythroid (BFU-E) growth was similarly decreased in bone marrow samples from the SIV+ animals. There was no change in the number of CFU-GM per plate with the removal of plastic adherent or T-cell mononuclear cell fractions. There was no increase in CFU-GM per plate growth with the addition of low dose GM-CSF (1 or 5 ng/mL) though there was a near 67% increase (48 to 80 CFU-GM per plate) with the addition of 100 ng/mL recombinant rhesus IL-3 and 100 ng/mL GM-CSF in SIV+ "sick" animals. Variation in frequency of CD34+ progenitor cells in SIV+ animals was seen, with 3.0% CD34+ cells in SIV- controls, 4.9% CD34+ cells in SIV+ "well" animals and 0.5% CD34+ progenitor cells in SIV+ "sick" monkeys (P < .01, each mean compared to the others). Finally, there was minimal evidence of SIV sequences by polymerase chain reaction in pooled cultured CFU-GM, and no evidence in flowcytometrically sorted CD34+ progenitor cells from selected animals. Thus, the SIV seropositive rhesus monkey appears to have similar hematopoietic aberrations as are found in HIV infected human subjects and may be an excellent model for studying the interaction of lentiviruses on the kinetics of blood formation.
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PMID:CD34+ and CFU-GM progenitors are significantly decreased in SIVsmm9 infected rhesus macaques with minimal evidence of direct viral infection by polymerase chain reaction. 769 May 18

The human recombinant hematopoietic growth factors have attracted widespread interest because of their potential efficacy in a number of clinical settings. Recombinant human erythropoietin is now an established therapy to treat and prevent the anemia associated with chronic renal failure in children and adults. This agent also shows extraordinary promise to stimulate erythrocyte production and reduce transfusion requirements in premature infants. Granulocyte and granulocyte-macrophage colony-stimulating factors stimulate the production and function of myeloid cells and have provided major clinical benefit to children with congenital disorders of neutrophil production. The myeloid growth factors also show great promise in reducing the duration and severity of neutropenias associated with cytotoxic cancer treatment and in improving granulocyte production in patients with human immunodeficiency virus infections.
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PMID:Hematopoietic growth factors in pediatrics. 769 Jun 36

Transfusions purportedly induce dysfunction of cell-mediated immunity in sickle cell anemia (SCA). We studied hematologic and lymphocytic indices in 173 human immunodeficiency virus (HIV)-negative subjects with SCA and 131 black controls. Children aged 1 to 7 years with SCA had leukocyte counts and percentages of granulocytes, monocytes, natural killer cells, and T-cell markers (CD2+CD11b+, CD4+CD26+, CD4+CD29+) that were significantly higher than those for control children. Percent total lymphocytes was decreased for this age group, but the total number of lymphocytes and T and B cell counts were similar to controls. Platelets were not increased. Adolescents (aged 8 to 17 years) and adults (aged > or = 18 years) with SCA had increased total leukocytes and monocytes and lymphocytes counts that remained level instead of decreasing, as did comparably aged controls. Lymphocyte subsets typically increased in count, but their percentage remained similar to children. The exception was CD56+ cell counts, which were increased in adolescents and adults. No lymphocytic subset change suggested impaired cellular immunity, and none could be related to transfusion. Prophylactically transfused patients had higher granulocyte counts, but these may arise from the complications of SCA itself.
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PMID:Blood transfusions and immunophenotypic alterations of lymphocyte subsets in sickle cell anemia. The Transfusion Safety Study Group. 771 80

We have previously shown that lymphocytic cells bind to cultured syncytiotrophoblast and that this may be important in the lymphocyte-mediated infection of trophoblast with the human immunodeficiency virus (HIV). Leukocyte-trophoblast adhesion may also have implications for normal trophoblast function. The following experiments were designed to characterize the adhesion systems that mediate the attachment of lymphocytic cells to trophoblast. Adhesion was assayed by labelling lymphocytic MOLT-4, clone 8 cells with the fluorescent marker, calcein-AM, and then incubating them with primary cultures of human syncytiotrophoblast. Adhesion was stimulated by pretreatment of the trophoblast cultures with several cytokines either alone or together. These included tumor necrosis factor-alpha (TNF-alpha), granulocyte/macrophage-colony stimulating factor (GM-CSF), interleukin-1 beta (IL-1 beta) and interferon-gamma (IFN-gamma). Stimulation was time- and dose-dependent. In contrast, preincubation of trophoblast cultures with anti-TNF-alpha antibodies for 2 days reduced MOLT adhesion by almost 50%. Preincubation with other anti-cytokine antibodies had no significant effect on adhesion. In other experiments, adhesion was measured in the presence of antibodies to known adhesion molecules. Adhesion was reduced by 50% in the presence of antibodies to alpha 4 integrin or beta 1 integrin. When present together, these antibodies reduced adhesion by almost 85%. Incubation in the presence of antibodies to the very late activation antigen-4 (VLA-4; alpha 4 beta 1 integrin) counter-receptors, VCAM-1 and CS-1, was without effect. Adhesion was also unaffected by antibodies to LFA-1, ICAM-1, ICAM-2, LFA-2, or LFA-3. These results suggest that adhesion is mediated by an adhesion system consisting of lymphocyte VLA-4 (alpha 4 beta 1) and an as yet unidentified counter receptor on trophoblast.
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PMID:Effect of cytokines and anti-adhesion molecule antibodies on the adhesion of lymphocytic cells to human syncytiotrophoblast. 780 71

Severe neutropenia and bone marrow (BM) morphologic abnormalities occur during experimentally induced primary infection with feline immunodeficiency virus (FIV), a lentivirus biologically similar to human immunodeficiency virus (HIV). To further characterize the mechanisms involved in this acute infection model of lentivirus-induced BM suppression, peripheral blood counts, histologic BM studies, and BM culture assays were performed on 12 cats that underwent necropsy at regular intervals postinoculation (PI) with FIV Petaluma. Plasma viremia developed at week 3 PI and neutropenia was initially detected at week 6 PI. Low neutrophil counts, but normal hematocrits and platelet counts, persisted through week 12 PI. Infected BM mononuclear cells and megakaryocytes were identified by in situ hybridization assays for FIV nucleic acids in BM sections of cats that underwent necropsy at weeks 4 to 12 PI, correlating with detection of soluble FIV p24 antigen and identification of infected mononuclear and macrophage cells in BM buffy-coat cell cultures from these cats. At weeks 1.5 to 4 PI, the mean frequencies (number per 10(5) BM mononuclear cells) of erythroid progenitors (erythroid colony-forming units [CFU-E] and erythroid burst-forming units [BFU-E] and granulocyte/macrophage progenitors (CFU-granulocyte/macrophage [CFU-GM]) were increased to 508 +/- 74, 143 +/- 24, and 110 +/- 17, respectively (n = 5 cats) as compared with controls (172 +/- 24, 86 +/- 26, and 44 +/- 10; n = 3 cats; P < .02), and the percentages of progenitors in the DNA-synthetic phase of the cell cycle were equivalent to controls. In contrast, the progenitor frequencies at weeks 6 to 12 PI were significantly decreased (72 +/- 16, 43 +/- 6, and 19 +/- 4, respectively; n = 7 cats; P < .01), and these progenitors were more frequently in S-phase. Autologous serum significantly inhibited (P < .05) the growth of CFU-GM in 6 of 9 cats and failed to support the maximal growth of BFU-E in 4 of 9 cats studied at weeks 4 to 12 PI, whereas no such abnormalities were observed in colony assays containing autologous sera from control cats (n = 3) or cats studied at weeks 1.5 or 3 PI (n = 3). In comparison, sera from FIV-infected cats did not inhibit the growth of normal, allogeneic progenitors. However, FIV serum frequently failed to support maximal in vitro growth of normal CFU-GM as compared with uninfected allogeneic sera, further suggesting a lack of progenitor growth-promoting substances in infected cat sera.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Marrow accessory cell infection and alterations in hematopoiesis accompany severe neutropenia during experimental acute infection with feline immunodeficiency virus. 784 16


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