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)

As a result of a pathophysiologically unexplainable bone marrow failure, most patients with progressive stages of human immunodeficiency virus (HIV) infection develop anemia, leukopenia, and thrombocytopenia. Besides the possibility of immune-mediated cytolysis or of direct viral infection of hemopoietic progenitor cells, the inhibitory influence of cytokines, for example interferon-alpha (IFN-alpha) and IFN-gamma, on hemopoiesis of HIV-infected patients might be considered as one parameter that contributes to myelosuppression. Therefore, progenitor cells from the bone marrow of HIV+ and HIV- persons were exposed to increasing concentrations of recombinant human IFN-alpha and IFN-gamma in methylcellulose assays. The colony formation of pluripotent (CFU-GEMM), erythroid (BFU-E), and granulocyte-macrophage (CFU-GM) progenitor cells was inhibited by both interferons. The 50% inhibitory doses (ID50) of IFN-alpha were 125.6 U/mL and 131.5 U/mL for BFU-E from HIV-infected persons and normal controls, respectively; the corresponding ID50 of IFN-alpha for CFU-GM growth was 1095.8 U/ml and above 3000 U/ml. When IFN-gamma was studied the ID50 was 341.7 and 2794.6 U/ml for BFU-E from HIV-infected and healthy individuals, respectively, while the ID50 for CFU-GM was above the highest dose levels in both groups (greater than 3000 U/ml). The ID50 for CFU-GEMM was below the lowest dose levels of IFN alpha and IFN gamma tested in both groups (less than 10 U/ml). The inhibitory effects could be specifically neutralized by monoclonal antibodies against IFN-alpha and IFN-gamma, thus confirming that the suppressive effects were due to the cytokines used.
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PMID:Influence of human recombinant interferon-alpha and interferon-gamma on bone marrow progenitor cells of HIV-positive individuals. 159 59

Anemia and neutropenia often develop in cats that are infected with the feline immunodeficiency virus (FIV), a lentivirus biologically similar to the human immunodeficiency virus (HIV). To assess the role of FIV in the pathogenesis of these abnormalities, marrow culture studies were performed on nine asymptomatic, hematologically normal cats that were chronically infected with FIV. In these experiments, the frequencies of granulocyte/macrophage progenitors (CFU-GM) and early and late erythroid progenitors (CFU-E and BFU-E, respectively) were equivalent to progenitor frequencies in simultaneously studied uninfected control cats. Asymptomatic FIV infection was not associated with a change in the cell-cycle kinetics of CFU-E, BFU-E, or CFU-GM, nor was there an alteration in the dose-response of BFU-E or CFU-GM to hematopoietic growth factors present in fibroblast-derived conditioned medium. Sera from FIV-infected cats supported progenitor growth in vitro as well as normal cat sera. Furthermore, there was no evidence that these sera contained complement-fixing antibodies that recognized hematopoietic progenitors. Therefore, these data show that the in vitro behavior of hematopoietic progenitors is not affected by FIV infection alone, and they are in agreement with recent evidence that human progenitors are not a major target of HIV infection. It is likely that factors associated with progressive immunodeficiency, opportunistic infections, nutritional deficiencies, or malignancies play significant roles in the cytopenias that develop during the symptomatic disease induced by FIV, and by analogy, HIV. Prospective marrow culture studies of FIV-infected cats that develop hematologic abnormalities should provide a valuable animal model of acquired immunodeficiency syndrome-associated hematologic disorders.
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PMID:Hematopoiesis in asymptomatic cats infected with feline immunodeficiency virus. 165 20

Early studies with the Gross passage A leukemia virus demonstrated that retroviral infection suppresses cellular and humoral immune responses. In extensive studies of the feline leukemia (FeLV) virus, which can induce profound immunodeficiency disease, are generative anemia and lymphoid, myeloid and erythroid neoplasia, the immunosuppressive effects of this retrovirus could be attributed to the actions of the retroviral envelope protein p15E. We found that a highly conserved, synthetic 17 amino acid peptide synthesized by Cianciolo and co-workers that is homologous to the hydrophilic portion of the otherwise hydrophobic transmembrane envelope protein can suppress polyclonal activation of B-cells, impair production of gamma- and alpha-interferon, inhibit production of interleukin-2, inhibit expression of IL-2 receptors, and suppress responses of cytotoxic lymphocytes. In analyses with inactivated preparations of the human immunodeficiency virus, with Pahwa et al. we demonstrated that purified non-infectious retrovirus and also retroviral proteins, in particular gp120, appeared to produce some of the immunosuppressive properties of HIV, particularly suppression of B-cell activation in response to known B-cell stimulants irrespective of T-cell influence, suppression of T-helper cell functions essential to B-lymphocyte responsiveness, and impaired function of immunoglobulin-secreting cells. Other investigators have also reported strong immunosuppressive or immunostimulatory influences for components of the HIV retrovirus and also gp120 through yet poorly elucidated but certainly complex actions on both T- and B-lymphocyte-mediated immune functions.
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PMID:In vitro immunomodulation and in vivo immunotherapy of retrovirus-induced immunosuppression. 166 53

Erythropoietin (EPO) is a major regulatory factor controlling red blood cell (RBC) production in humans. Although other humoral factors can alter the proliferation of committed early erythroid progenitors in vitro, no factor other than EPO has been clearly shown to induce proliferation of these cells in vivo. In a clinical trail of recombinant granulocyte colony-stimulating factor (G-CSF) and recombinant EPO in patients with advanced human immunodeficiency virus (HIV) infection, we noted reticulocytosis and increases in hemoglobin when G-CSF was administered before the administration of EPO. Subsequent studies demonstrated a significant increase in circulating burst forming unit-erythron (BFU-E) during daily recombinant G-CSF therapy. This increase was both time- and dose-dependent. The magnitude of increase in BFU-E correlated with the magnitude of increase in neutrophils and was associated with a mean increase in reticulocytes of 32,363/microL and a significant increase in mean hemoglobin of 1.04 +/- 0.34 g/dL over an 18-day interval. There was a significant increase in iron binding capacity and decreases in iron saturation and ferritin levels. In patients who were not recently transfused, there was an associated fall in endogenous erythropoietin levels. The increase in RBC production was most marked in patients who were severely anemic, transfusion-dependent, and who had elevated pretreatment EPO levels. There was no correlation between the increase in BFU-E and endogenous EPO levels or the time since last dose of zidovudine. The addition of recombinant EPO therapy three times weekly to patients did not result in further significant increases in BFU-E but did significantly increase hemoglobin. Our data suggest that recombinant G-CSF may be one of the hematopoietic factors that influences production of BFU-E and RBCs in humans.
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PMID:Recombinant human granulocyte colony-stimulating factor increases circulating burst forming unit-erythron and red blood cell production in patients with severe human immunodeficiency virus infection. 169 97

3'-Azido-2',3'-dideoxy-5-methylcytidine (CS-92, AzddMeC) is an antiviral nucleoside analogue structurally related to 3'-azido-3'-deoxythymidine (AZT). CS-92 is a potent and selective inhibitor of HIV-1 reverse transcriptase and HIV-1 replication in human lymphocytes and macrophages. The EC50 for CS-92 in HIV-1-infected human PBM cells was 0.09 microM. In HIV-1-infected human macrophages, the EC50 was 0.006 microM. This compound was also effective against human immunodeficiency virus type 2 in lymphocytes. The replication of Friend murine virus was only weakly inhibited, and no effect was observed against herpes simplex virus type 1 and type 2 and coxsackievirus B4. CS-92 was not toxic to PBM or Vero cells when tested up to 200 microM and was, furthermore, at least 40 times less toxic to granulocyte-macrophage and erythroid precursor cells in vitro than was AZT. The interaction of the 5'-triphosphate of CS-92 with HIV-1 reverse transcriptase indicated competitive inhibition (the inhibition constant, Kis, was 0.0093 microM) with a 30-fold greater affinity for CS-92-TP than for ddCTP. CS-92-TP inhibited HIV-1 reverse transcriptase by 50% at a concentration 6,000-fold lower than that which was required for a similar inhibition of DNA polymerase alpha. Pharmacokinetic studies showed that CS-92 was not deaminated to AZT in rats, but this compound was found to have a half-life of 2.7 hours. In rhesus monkeys, however, a compound with a retention time and ultraviolet spectra characteristics similar to AZT was detected. The mean half-life in rhesus monkeys for CS-92 was 1.52 and 1.74 h after intravenous and oral administration, respectively, and the oral bioavailability was about 21 percent. Additional preclinical studies with CS-92 will determine the ultimate utility of this antiviral agent for the treatment of HIV-1 infections.
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PMID:Antiretroviral activity, biochemistry, and pharmacokinetics of 3'-azido-2',3'-dideoxy-5-methylcytidine. 170 74

The anti-human immunodeficiency virus (HIV) activity and hemopoietic toxicity of zidovudine (AZT) and didanosine (dideoxyinosine;ddI), alone and in combination, were assessed in a variety of cell types. AZT was more potent than ddI as an inhibitor of HIV in vitro. Synergistic inhibition of HIV by the combination of these agents was observed in MT4 cells, peripheral blood lymphocytes, and macrophages. Toxicity assessment in vitro by using progenitor (erythroid and granulocyte-macrophage) colony-forming assays with normal human bone marrow showed ddI to be less toxic than AZT. Addition of inhibitory concentrations of ddI to AZT resulted in additive inhibition of progenitor CFUs. These in vitro findings suggest that combinations of ddI and AZT at appropriately modified doses may provide an enhanced degree of selectivity in anti-HIV chemotherapy.
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PMID:Anti-human immunodeficiency virus synergism by zidovudine (3'-azidothymidine) and didanosine (dideoxyinosine) contrasts with their additive inhibition of normal human marrow progenitor cells. 170 77

Hematopoietic dysfunction with peripheral cytopenias is a common complication of human immunodeficiency virus (HIV) infection. Symptomatic anemia is the most common cytopenia and occurs in the presence and absence of myelosuppressive drug therapy such as zidovudine. Drug-induced neutropenia and immune thrombocytopenia are also frequent and occur in up to 50% of acquired immunodeficiency syndrome (AIDS) patients. Attempts to reduce the impact of bone marrow failure have focused on dose reduction of zidovudine, ganciclovir, and chemotherapy, and the use of recombinant hematopoietic hormones such as erythropoietin (EPO) and granulocyte colony-stimulating factor (G-CSF). Despite these maneuvers, approximately 30% of patients with AIDS receiving zidovudine will become transfusion-dependent. This has led to investigations of other cytokines that may increase blood cell formation. The recent identification of decreased number and proliferation of hematopoietic progenitors in patients with HIV infection suggests that agents which have activity on progenitor cell pools may have clinical utility. We demonstrate that human stem cell factor (HuSCF) increases burst-forming unit-erythroid (BFU-E), colony-forming unit-granulocyte-monocyte (CFU-GM), and CFU-Mix formation in vitro in normal and HIV-infected individuals. HuSCF also decreases the sensitivity of BFU-E to inhibition by zidovudine without altering HIV replication in lymphocytes or monocytes, altering peripheral blood mononuclear cell proliferation to phytohemagglutinin (PHA) and interleukin-2 (IL-2) or altering the effectiveness of zidovudine or dideoxyinosine in inhibiting HIV replication in lymphocytes or monocytes. These studies suggest that HuSCF may have clinical utility in HIV infection as an adjunctive treatment for HIV-related cytopenias.
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PMID:Potential use of human stem cell factor as adjunctive therapy for human immunodeficiency virus-related cytopenias. 172 Jun 98

Long-term bone marrow cultures (LTBMC) have been infected by two isolates of human immunodeficiency virus type 1 (HIV-1) (HIV-1 LAV and HIV-1 NDK) at multiplicities of infection ranging from 10(2) to 2.10(6) tissue culture infectious units (TCIU) per 10(6) bone marrow mononuclear cells (BMMNC). These infected cells are nonproducer cells and the viruses can be rescued by coculture with peripheral blood lymphocytes, cord blood lymphocytes, or BMMNC and not by the CEM cell line. HIV-1 clearly is not cytopathic for these cells. Following production and growth of erythroid burst-forming units (BFU-E) and erythroid colony-forming units (CFU-E) for at least 6 weeks after infection with HIV-1 NDK, colony assays displayed a 50% inhibition of BFU-E production during 3 weeks of LTBMC. This was followed by a stimulation phase. On the contrary, HIV-1 LAV induces a 150% stimulation of BFU-E production, followed by 50% inhibition. Production of CFU-E was inhibited by 80-100% with the two isolates of HIV-1 after four weeks of LTBMC. Stimulatory and inhibitory activities were recovered from supernatants of infected LTBMC and lymphoid CEM cell lines, suggesting that HIV-1 induces release of a humoral factor responsible for disruption of hemopoietic progenitor cell production in vitro and consequently for hematologic abnormalities in AIDS patients.
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PMID:Modulation of normal human erythropoietic progenitor cells in long-term liquid cultures after HIV-1 infection. 173 41

The in vitro growth of both circulating granulocyte-macrophage (CFU-GM) and erythroid (BFU-E) progenitor cells was assessed in 29 individuals infected with the human immunodeficiency virus (HIV) at different stages of infection. The effects of autologous T lymphocytes, adherent cells, and serum on the in vitro growth of hematopoietic progenitor cells were also investigated. Compared with normal controls, baseline growth was significantly reduced for both CFU-GM and BFU-E in HIV-infected patients, independent of the clinical stage of the disease. In HIV-infected subjects depletion of autologous T cells was associated with a significant increase of progenitor cell growth. Similar results were observed after selective depletion of CD8+ T cells, while readdition of T cells to T-depleted mononuclear cells reduced the number of CFU-GM. A dose-dependent colony inhibitory activity was found in conditioned medium of T cells from HIV-infected subjects. Neither autologous adherent cells nor serum from either HIV+ or HIV- subjects had any significant effect on the in vitro growth of CFU-GM. These results indicate that the in vitro growth of circulating hematopoietic progenitor cells is impaired even in the early stages of HIV infection, and that autologous T cells exert an inhibitory effect on the in vitro growth of progenitor cells, possibly via soluble mediator(s).
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PMID:Impaired in vitro growth of peripheral blood hematopoietic progenitor cells in HIV-infected patients: evidence of an inhibitory effect of autologous T lymphocytes. 175 93

Erythropoietin is a glycoprotein hormone that plays a vital role in erythropoiesis. It is mainly produced in the fetal liver till the third trimester of pregnancy. At that point, the kidney interstitium takes over this function and becomes the main source of erythropoietin. Hypoxia stimulates erythropoietin production by a mechanism that may require a heme protein as a second messenger. Erythropoietin stimulates the maturation of erythroid precursors (colony-forming unit-erythroid and burst-forming unit-erythroid) via at least two types of cell surface receptors. The higher-affinity receptors appear to be more important in modulating the effects of erythropoietin in vivo. Changes in intracellular calcium may ultimately mediate the action of erythropoietin on erythroid precursors. A specific and sensitive radioimmunoassay is now available for accurately measuring erythropoietin levels. All forms of erythrocytosis except polycythemia vera are associated with elevated erythropoietin levels. Levels are also high in cord blood obtained following fetal asphyxia. Reduced levels are seen in patients with anemia due to renal diseases. The response of erythropoietin to the degree of anemia appears to be attenuated in patients with cancer, chronic diseases, and human immunodeficiency virus (HIV) infection. Erythropoietin has been successfully used for treating patients with anemia due to renal failure. Its use has also been approved for the treatment of anemia patients receiving zidovudine for HIV infection. Encouraging results have been observed when erythropoietin was used to treat anemia due to rheumatoid arthritis, hematological malignancies, and prematurity. It has also been used to increase the yield of autologous blood collected prior to an elective surgical procedure. However, it has not proved to be useful in sickle cell anemia and myelodysplastic syndromes.
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PMID:Erythropoietin. Biology and clinical applications. 178 66


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