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)

In this study, we examined the potential role of the human immunodeficiency virus (HIV) tat protein in causing the hematopoietic abnormalities frequently observed in HIV-infected individuals. Recombinant tat (r-tat) protein, at concentrations up to 10 micrograms/mL, did not display any stimulatory or inhibitory effect on the survival/proliferative capacity of CD34+ hematopoietic progenitor cells, purified from normal bone marrow (BM). However, exposure of r-tat protein (at concentrations between 10 ng/mL and 10 micrograms/mL) to enriched normal BM macrophages induced the production of a factor(s) in conditioned media that inhibited the in vitro growth of CD34+ cells in liquid cultures and of immature hematopoietic progenitors (day 14 colony-forming unit-granulocyte-macrophage, burst-forming unit-erythroid, and colony-forming unit-megakaryocyte) in semisolid assays. Pre-exposure of r-tat protein with a monoclonal neutralizing anti-tat antibody completely abrogated the inhibitory activity present in BM macrophage culture supernatants. The main factor responsible for this suppressive activity was transforming growth factor-beta 1 (TGF-beta 1), as shown by the ability of a polyclonal anti-TGF-beta 1 neutralizing antibody to almost completely reverse the suppressive effect of BM macrophage supernatants on CD34+ cells. TGF-beta 1 bioassays showed that exposure of r-tat protein to BM macrophages significantly increased the levels of both active and latent forms of TGF-beta 1. These results indicate that the production of TGF-beta 1, one of the most potent negative regulator of hematopoiesis, is increased by HIV tat protein and that such increase could contribute to the derangement of the hematopoietic system in HIV-infected individuals.
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PMID:tat protein stimulates production of transforming growth factor-beta 1 by marrow macrophages: a potential mechanism for human immunodeficiency virus-1-induced hematopoietic suppression. 128 86

In this report the role played by human immunodeficiency virus type-1 (HIV-1) in the pathogenesis of HIV-1-related thrombocytopenia was investigated. CD34+ hematopoietic stem/progenitor cells were purified from the bone marrow (BM) of HIV-1(+) thrombocytopenic patients, HIV-1(+) nonthrombocytopenic individuals, HIV-1(-) patients with immune thrombocytopenic purpura, and HIV-1(-) normal donors. CD34+ cells from HIV-1(+) thrombocytopenic individuals alone showed a reduced capacity to give rise to megakaryocytic colonies (CFU-Meg) and also a progressive and significant decline in cell number when placed in liquid culture containing recombinant human interleukin-3 (rIL-3). This decline involved not only megakaryocyte but also erythroid and granulocyte/macrophage progenitors. The defects in megakaryocyte colony formation and CD34+ cell growth did not result from a productive HIV-1 infection of CD34+ cells. Moreover, HIV-1 DNA was absent from CD34+ cells in 10 of 12 thrombocytopenic patients examined. On the other hand, the decreased survival/proliferation of CD34+ cells in liquid culture, within the HIV-1(+) thrombocytopenic patients, was correlated with the presence of HIV-1 p24 antigen in BM plasma. These results demonstrate an impairment of CD34+ cells in HIV-1(+) individuals presenting thrombocytopenia as the only hematologic manifestation. Furthermore, these findings suggest that increased viral replication in the BM microenvironment may cause this impairment and possibly contributes to HIV-induced thrombocytopenia.
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PMID:Impaired in vitro growth of purified (CD34+) hematopoietic progenitors in human immunodeficiency virus-1 seropositive thrombocytopenic individuals. 137 10

Hematopoietic progenitor (CD34+) cells were purified from the bone marrow of 6 human immunodeficiency virus (HIV) type 1-seropositive cytopenic patients and 10 healthy donors. HIV-1-seropositive patients showed a reduced number of granulocyte/macrophage, erythroid, and megakaryocyte progenitors and also a progressive and significant decline of numbers of CD34+ cells in liquid culture, which did not result from a productive or latent HIV-1 infection of CD34+ cells. However, all HIV-1-seropositive patients showed signs of active viral replication at the bone marrow level. Moreover, virus isolates from 3 HIV-1-seropositive patients showed a dose-dependent inhibition on growth of normal CD34+ cells. This suppressive activity was almost completely reversed by incubating the virus isolates with an anti-gp120 polyclonal antibody before adding to normal CD34+ cells.
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PMID:Evidence for a human immunodeficiency virus type 1-mediated suppression of uninfected hematopoietic (CD34+) cells in AIDS patients. 138 6

Compact, lobulated megakaryocyte nuclei, apparently denuded of cytoplasm (naked nuclei), have been reported to be markedly increased in the bone marrow of persons infected with human immunodeficiency virus (HIV). We have confirmed this observation and have developed a useful diagnostic index, the naked nucleus ratio, to characterize the bone marrow of individuals who are infected with HIV. The naked nucleus ratio, calculated as the average number of naked nuclei per high-power field divided by the average number of intact megakaryocytes per high-power field, has a sensitivity of 97.9% and a specificity of 96.4% for patients with HIV infection. In our patients with a 62.6% prevalence of HIV infection, the predictive value of a positive test was 97.9% and the predictive value of a negative test was 96.4%. An increase in the naked nucleus ratio above 10%, without specific changes in the bone marrow, should raise or may confirm the suspicion of HIV infection.
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PMID:Naked megakaryocyte nuclei as an indicator of human immunodeficiency virus infection. 141 41

We studied human megakaryocytes to determine if they both expressed and synthesized Fc gamma and CD4 membrane receptors. The strategy employed relied on demonstration of receptor protein and mRNA in megakaryocytes present in freshly made marrow smears, or in megakaryocytes isolated from aspirated normal bone marrow by counterflow centrifugal elutriation. Protein was detected immunochemically, whereas mRNA was detected either by in situ hybridization, or by reverse transcription, polymerase chain reaction (RT-PCR). Using these methods CD4 and Fc gamma RII protein and mRNA were detected in most megakaryocytes. Fc gamma RI and Fc gamma RIII protein was not detected in these cells. Megakaryocytes were also cultured with recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF) to determine the effect of this growth factor on Fc gamma RII expression. As has been noted in cells of the monocyte-macrophage lineage, exposure to rhGM-CSF resulted in a significant increase in the level of megakaryocyte Fc gamma RII mRNA and protein. These observations are significant because they provide a physiologic basis for known viral trophism displayed by megakaryocytes. They are also of interest because they suggest that alternative portals exist for entry of human immunodeficiency virus (HIV-1) into megakaryocytes and that such infection may play a role in acquired immunodeficiency syndrome (AIDS)-related thrombocytopenia.
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PMID:Expression of Fc gamma RII and CD4 receptors by normal human megakaryocytes. 153 89

When fungi infect the bone marrow, typically they are associated with granuloma formation and/or necrosis, and the fungi are found within histiocytes or admixed with necrotic debris. Recently two bone marrow biopsy specimens were encountered in which fungi were confined to the cytoplasm of megakaryocytes, a finding not previously reported in the literature. The first case was that of a 46-year-old man with pulmonary histoplasmosis and no known immunodeficiency. The second was that of a 38-year-old man with the acquired immune deficiency syndrome and cryptococcal meningitis. In the first case, many megakaryocytes contained fungal forms consistent with Histoplasma. In the second, one small cluster of megakaryocytes contained several budding yeast consistent with Cryptococcus. Neither marrow biopsy specimen had necrosis, granulomas, or histiocytic infiltration. In both cases, because of the unusual localization of the fungi, they were initially overlooked. The bone marrow may contain fungi even in the absence of abnormalities suggesting fungal infection on routinely stained sections. A silver stain or a periodic acid--Schiff stain should be performed on all marrow biopsy specimens in cases of known or suspected fungal infection outside the marrow. The phenomenon of megakaryocyte emperipolesis is well known, and this process may be responsible for the apparent ability of megakaryocytes to internalize fungi.
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PMID:Fungi in megakaryocytes. An unusual manifestation of fungal infection of the bone marrow. 171 95

The pathophysiology of thrombocytopenia in the acquired immune deficiency syndrome has not been elucidated completely. Many findings in these patients are identical to those with immune thrombocytopenic purpura. However, recent findings in acquired immune deficiency syndrome patients including the effect of zidovudine on platelet count and the demonstration of ultrastructural changes and viral RNA in megakaryocytes, have suggested that the human immunodeficiency virus may directly infect megakaryocytes, and play a role in acquired immune deficiency syndrome-related thrombocytopenia. To investigate further the mechanism of decreased platelet counts in human immunodeficiency virus-infected patients, the platelet volume-number relationship and corresponding bone marrow findings in 34 patients infected with human immunodeficiency virus were studied. Parameters evaluated included platelet count and mean platelet volume; bone marrow cellularity, megakaryocyte number, and number and percentage of denuded megakaryocyte nuclei. Two thirds of the platelet counts were low, and of these 92% had an inappropriately low mean platelet volume. These individuals had a platelet-volume number relationship that is very similar to that seen in myelosuppressive disorders. In addition, more than 90% of the bone marrows from thrombocytopenic patients had either normal or decreased numbers of megakaryocytes. These observations provide additional evidence to support the hypothesis that the pathophysiology of human immunodeficiency virus-associated thrombocytopenia may be due, at least in part, to a direct effect on the megakaryocytes.
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PMID:The platelet volume-number relationship in patients infected with the human immunodeficiency virus. 189 25

We investigated the in vitro growth of circulating progenitors from mononuclear nonadherent cells (MNAC) and T-depleted MNAC (non-T-MNAC) in the peripheral blood (PB) of 20 human immunodeficiency virus type 1 (HIV-1) seropositive subjects, compared with 12 normal adult volunteers, in order to clarify whether the loss of hemopoietic progenitors described in the bone marrow (BM) of AIDS-related complex (ARC)/AIDS patients could occur in PB before the AIDS stage, only those patients at the early stages of the disease who had never undergone cytotoxic therapy were considered in the study. We found a significant reduction in the number of granulocyte-macrophage progenitors (granulocyte-macrophage colony-forming units, CFU-GM; p less than 0.001), megakaryocytic progenitors (megakaryocyte colony-forming units, CFU-MK; p less than 0.001) and erythroid progenitors (erythroid burst-forming units, BFU-E; p less than 0.05) in non-T-MNAC cultures of PB from HIV-1 seropositive subjects compared with normal PB control cultures. Although most of our patients had an inverted CD4/CD8 ratio and a marked reduction in the absolute number of CD4+ cells, there was no correlation with the absolute number of CD4+ cells or with the CD4/CD8 ratio. The loss of hemopoietic progenitors in PB seemed to occur earlier than in BM, because the hemograms of the patients considered in the study were normal in most cases.
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PMID:Early loss of circulating hemopoietic progenitors in HIV-1-infected subjects. 197 Sep 62

The human immunodeficiency virus (HIV) is capable of infecting certain cells of hematopoietic lineage, particularly monocyte-macrophages and T lymphocytes. Recently, the possibility that cells of megakaryocytic lineage are susceptible to HIV infection has been raised. We have characterized infection of the permanent megakaryocytic cell line CMK by HIV in vitro. CMK cells were easily infected by HIV type 2 (HIV-2), producing significant amounts of virus in culture. Infection appeared to be mediated by the CD4 surface antigen on CMK cells. Three different strains of HIV-1 were able to minimally infect CMK cells, suggesting there may be isolates of HIV tropic for megakaryocytes. Infection of CMK cells led to downregulation of the CD4 surface antigen but no discernable change in expression of megakaryocyte-associated proteins glycoprotein Ib and glycoprotein IIb/IIIa. These observations support the likelihood that megakaryocytes are susceptible to HIV infection, and cell lines of megakaryocytic origin may provide a useful model to study effects of the retrovirus on megakaryocyte function.
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PMID:Human immunodeficiency virus infection of megakaryocytic cells. 199 Nov 65

Parvovirus B19 infection leads to transient aplastic crises in individuals with chronic hemolytic anemias or immunodeficiency states. An additional unexplained sequela of B19 infection is thrombocytopenia. Because B19 is known to have a remarkable tropism for human erythropoietic elements, and is not known to replicate in nonerythroid cells, the etiology of this thrombocytopenia is uncertain. We sought to define the pathobiology of B19-associated thrombocytopenia by examining the role of B19 on in vitro megakaryocytopoiesis. B19 infection of normal human bone marrow cells significantly suppressed megakaryocyte (MK) colony formation compared with mock-infected cells. No such inhibition was observed with a nonpathogenic human parvovirus, the adeno-associated virus 2 (AAV). The B19-MK cell interaction was also studied at the molecular level. Whereas low-density bone marrow cells containing erythroid precursor cells supported B19 DNA replication, no viral DNA replication was observed in B19-infected MK-enriched fractions as determined by the presence of viral DNA replicative intermediates on Southern blots. However, analysis of total cytoplasmic RNA isolated from B19-infected MK fractions showed a low-level expression of the B19 genome as detected by quantitative RNA dot blots as well as by Northern analysis. Furthermore, a frame-shift mutation in a recombinant AAV-B19 hybrid genome segment that encodes the viral nonstructural (NS1) protein significantly reduced the observed inhibition of MK colony formation. These studies indicate tissue-tropism of B19 beyond the erythroid progenitor cell, and lend support to the hypothesis that B19 genome expression may be toxic to cell populations that are nonpermissive for viral DNA replication.
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PMID:Parvovirus B19-induced perturbation of human megakaryocytopoiesis in vitro. 214 78


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