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)

Three human T cell clones (TCC) specific for purified protein derivative of Mycobacterium tuberculosis were incubated in the presence of polybrene and phytohemagglutinin with irradiated mononuclear cells from one individual exhibiting seropositivity for human immunodeficiency virus (HIV) and high levels of circulating p24 antigen. After three weeks, TCC showed HIV integration in their DNA, as shown by polymerase chain reaction analysis and Southern blot technique. All the three HIV-infected TCC maintained their ability to recognize the specific antigen, even if their proliferative ability was reduced. The ability of the HIV-infected TCC to produce IL-2, IL-4 and IFN-gamma in response to phorbol myristate acetate plus anti-CD3 monoclonal antibody was decreased, whereas their ability to produce TNF-alpha was unaffected or even enhanced. Two out of the three HIV-infected TCC showed the ability to provide helper function for polyclonal immunoglobulin production when cocultured with autologous B cells in the absence of any stimulant. These data suggest that in vitro infection of normal human TCC may provide a useful model for the study of immunological alterations induced by HIV.
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PMID:In vitro infection with HIV of antigen-specific T cell clones derived from HIV-seronegative individuals. Effects on cytokine production and helper function. 171 99

The effects of human immunodeficiency virus 1 (HIV-1) infection on cellular differentiation and NF-kappa B DNA binding activity have been investigated in a new model of myeloid differentiation. PLB-985 cells represent a bipotential myelomonoblastic cell population capable of either granulocytic or monocytic differentiation after induction with appropriate inducers. By virtue of the presence of CD4 on the cell surface, PLB-985 cells were chronically infected with HIV-1 strain IIIB. PLB-IIIB cells clearly possessed a more monocytic phenotype than the parental myeloblasts, as determined by differential staining, increased expression of the myeloid-specific surface markers, and transcription of the c-fms proto-oncogene. NF-kappa B binding activity was inducible by tumor necrosis factor and phorbol myristate acetate in PLB-985. However, in PLB-IIIB cells, constitutive expression of a novel NF-kappa B complex was detected, composed of proteins ranging between 70 and 110 kD. These proteins interacted specifically with the symmetric NF-kappa B site from the interferon beta (IFN-beta) promoter. Mutations affecting the 5' guanine residues of the kappa B site were unable to compete for these NF-kappa B-related proteins. Inducibility of endogenous IFN-beta and IFN-alpha RNA was also increased in PLB-IIIB cells. These studies indicate that HIV-1 infection of myelomonoblastic cells may select for a more mature monocytic phenotype and that unique subunit associations of NF-kappa B DNA binding proteins may contribute to differential NF-kappa B-mediated gene expression.
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PMID:Induction of monocytic differentiation and NF-kappa B-like activities by human immunodeficiency virus 1 infection of myelomonoblastic cells. 174 Jun 63

Acemannan (ACE-M), a beta-(1,4)-linked acetylated mannan, was evaluated for in vitro activity against human immunodeficiency virus type 1 (HIV-1). Castanospermine (CAS), deoxymannojirimycin (DMN), swainsonine (SWS), azidothymidine (AZT), and dideoxythymidine (DDC) were tested in parallel as control compounds. In vitro antiviral efficacy of ACE-M was evaluated in a variety of cell lines including human peripheral mononuclear, CEM-SS1 and MT-2(2) cells. The virus strain, number of infectious units per cell, and target cell line were important factors in determining the degree of inhibition of viral cytopathic effect in the presence of ACE-M and other control compounds tested. Maximum inhibitory effect was observed in CEM-SS cells infected with the RFII strain of HIV-1. This inhibitory effect was determined to be concentration-dependent. Assay design included primary screening to measure cell viabilities of infected target cells in the presence and absence of test compounds. When tested on HIV-1/RFII-infected CEM-SS cells, the 50% inhibitory effect of CAS (IC50 = 28), an inhibitor of alpha-glucosidase I, was determined to be similar to that observed for ACE-M (IC50 = 45). However, DMN and SWS, inhibitors of mannosidase I and II, tested in parallel to CAS and ACE-M, exhibited no IC50 values. Antiviral potential of ACE-M as an inhibitor of syncytia formation was also explored using CEM-SS cells. Suppression of syncytia formation was observed at an ACE-M concentration of 31.25 micrograms/ml, and complete inhibition was observed at 62.5 micrograms/ml. In addition, HIV-1 RNA levels were studied to establish the antiviral potential of ACE-M in vitro.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Inhibition of AIDS virus replication by acemannan in vitro. 176 65

We have characterized CD4-CD8- double-negative (DN) alpha beta TCR+ T cells from a patient with immunodeficiency, lymphocytosis, lymphadenopathy, and hepatosplenomegaly. The majority of peripheral blood lymphocytes were DN alpha beta TCR+ T cells as evaluated by FACS and biochemical analysis. The DN T cells showed the following phenotype: alpha beta TCR+, gamma delta TCR-, CD2+, CD3+, CD4-, CD5+, CD7-, CD8-, CD16-, CD25-, CD26-, CD28+, CD45RO-, CD45RA+, CD57+, and HLA-DR+. Both southern blot analysis of TCR genes and FACS analysis applying a panel of V beta and V alpha monoclonal antibodies (MoAbs) indicated a polyclonal T-cell expansion. Thymic biopsy showed normal histology, whereas lymph node biopsy samples showed altered histological and immunohistological patterns with markedly expanded paracortical areas containing the DN T cells of the same phenotype as found in peripheral blood T cells. In functional studies, the DN T cells showed a profoundly reduced proliferative response upon stimulation with mitogens as well as MoAbs against the TCR/CD3 complex, CD2, and CD28, respectively. Addition of exogenous interleukin-2 (IL-2) only minimally augmented the proliferative response. In contrast, the addition of a combination of Ca2+ ionophore and phorbol 12-myristate 13-acetate (PMA) restored the proliferative response of the DN T cells to almost normal levels. This observation strongly suggests that the protein kinase C activity of the DN T cells was intact, but that the normal mechanism for transmembrane signal transduction was impaired in these unusual DN T cells.
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PMID:Phenotypical and functional characterization of double-negative (CD4-CD8-) alpha beta T-cell receptor positive cells from an immunodeficient patient. 183 26

Human immunodeficiency virus 1 (HIV-1) protease is an aspartyl protease composed of two identical protomers linked by a four-stranded antiparallel beta-sheet consisting of the NH2- and COOH-terminal segments (Weber, I.T. (1990) J. Biol. Chem. 265, 10492-10496). Kinetic analysis of the HIV-1 protease-catalyzed hydrolysis of a fluorogenic substrate demonstrates that the enzyme is an obligatory dimer. At pH = 5.0, 0.1 M sodium acetate, 1 M NaCl, 1 mM EDTA buffer, 37 degrees C, the equilibrium dissociation constant, Kd = 3.6 +/- 1.9 nM. We found that the tetrapeptide Ac-Thr-Leu-Asn-Phe-COOH, corresponding to the COOH-terminal segment of the enzyme, is an excellent inhibitor of the enzyme. Kinetic analysis shows that the inhibitor binds to the inactive protomers and prevents their association into the active dimer (dissociative inhibition). The dissociative nature of this inhibition is consistent with the results obtained from sedimentation equilibrium experiments in which the apparent molecular weight of the enzyme was observed to be 20,800 +/- 1,500 and 12,100 +/- 300, in the absence and presence of the COOH-terminal tetrapeptide, respectively. The dissociation constant of the protomer-inhibitor complex is Ki = 45.1 +/- 1.8 microM. This is the first kinetic analysis and direct experimental demonstration of noncovalent dissociative inhibition.
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PMID:Dissociative inhibition of dimeric enzymes. Kinetic characterization of the inhibition of HIV-1 protease by its COOH-terminal tetrapeptide. 187 17

Adherent cells from human immunodeficiency virus (HIV)-infected subjects but not from normal blood donors, patients with Gram-positive or -negative bacteremia, active tuberculosis, toxoplasmosis, pulmonary aspergillosis, and cytomegalovirus infection produce spontaneously an activity which inhibits alpha chain of interleukin-2 (Tac) expression and interleukin 2 (IL-2) production by normal activated T cells and IL-2 production by these cells. A similar biologic activity was detected in culture supernatants of in vitro HIV-I-infected normal adherent and leukemic U937 cells. Tac-inhibitory activity is not cytotoxic and it could be detected in serum-free conditioned media. Recombinant granulocyte/macrophage colony-stimulating factor and phorbol myristate acetate stimulation of patients' and normal adherent cells did not enhance specifically the production of the Tac inhibitor. Biologically active conditioned media did not contain infectious virus as well as secreted p24, gp120 viral proteins; the biologic activity could not be abolished by anti-p24, anti-gp120, and anti-nef monoclonal antibodies or human purified polyclonal anti-HIV IgG. Gel filtration of conditioned media followed by anion exchange chromatography resulted in a 1,200-fold degree of purification and revealed that the biologically active molecule was cationic. Sodium dodecyl sulfate polyacrylamide gel electrophoresis of this fraction and gel elution of the proteins showed that the biologic activity was associated with a 29-kD protein which was distinct from alpha- or gamma-interferon, tumor necrosis factor-alpha, and prostaglandin E2. The above findings demonstrate the production of inhibitory factor(s) during HIV infection, which might be involved in the pathogenesis of the patients' immune defect.
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PMID:Biological and biochemical characterization of a factor produced spontaneously by adherent cells of human immunodeficiency virus-infected patients inhibiting interleukin-2 receptor alpha chain (Tac) expression on normal T cells. 190 71

The effects of oxygen deprivation, or anoxia, on human immunodeficiency virus (HIV-1) expression in chronically (ACH.2) and acutely (H9/HIV-1-IIIB) infected cell lines was investigated. Temporary cellular anoxia has previously been shown to activate transcription of endogenous type C leukemia virus sequences, resulting in a significant increase in retroviral RNA within the cell (1). Here we report a 15-fold increase in HIV-1-specific RNA in unstimulated ACH.2 T cells within 24 h of anoxia. This induction of RNA is accompanied by an accumulation of intracellular p24 gag protein as well as an increase in envelope protein. Anoxia induces a further increase in total HIV-1 RNA in ACH.2 cells prestimulated to produce virus by phorbol 12-myristate 13-acetate and in H9 T cells acutely infected with HIV-1-IIIB. The induction of RNA in ACH.2 cells appears to be reversible. Anoxic culture for 24 h followed by a 24-h re-oxygenation period results in a return to "resting state" levels of HIV-1 RNA. These data indicate that oxygen tension within the cellular environment modulates HIV-1 expression, providing a model system in which to study the reversible regulation of HIV-1 RNA and viral gene products within the cell.
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PMID:Anoxia induces human immunodeficiency virus expression in infected T cell lines. 190 63

Trans-activating activities of certain cellular promoter/enhancer genes may reflect the underlying mechanism for cellular differentiation. We have used two promonocytic leukemia cell lines, U937 and HL-CZ, which differ in their differentiation antigen expression. While both cell lines express CD15 antigen, only the former expresses both CD4 and CD10 antigens. These phenotypes suggest that these two cell lines appear to be arrested at different stages of differentiation. Some regions of the long terminal repeat (LTR) of human immunodeficiency virus-1 (HIV-1) contain nucleotide sequences which bind cellular trans-activating factors such as NF-kappa B and Sp1. These sequences are also present in cellular regulatory gene sequences. The cell lines have been transfected by electroporation with a nested series of deletion mutants containing different lengths of the promoter/enhancer region for HIV-LTR. The promoter/enhancer region has been linked to a 'reporter' chloramphenicol acetyl transferase (CAT) gene. We have found that promoter/enhancer trans-activation is markedly enhanced by treating transfected cells with 12-O-tetradecanoylphorbol-13-acetate (TPA), while similar treatment with tumor necrosis factor-alpha (TNF alpha) slightly enhanced activation. U937 cells always showed much greater transactivating activities than did HL-CZ cells. Deletion of a negative regulatory element (NRE) from the LTR resulted in an enhanced transactivation, while deletions affecting NF-kappa B and/or Sp1 binding sites markedly reduced transactivation. Deletion of both NRE and NRF, a second negative regulatory factor binding site, from the LTR restored the transactivation. However, in the presence of TPA, deletion of NRE sequence without concomitant deletion of the downstream NRF binding sequence was sufficient for recovering transactivation. Since these two cell lines have shown subtle differences in these responses, it may be speculated that monocytes at different stages of differentiation may respond in different ways, qualitatively and/or quantitatively, to signal transduction factors involved in the transactivation of cellular genes.
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PMID:Regulation of cellular trans-activating activities in two different promonocytic leukemia cell lines. 191 29

Tumor necrosis factor alpha (TNF-alpha) is expressed in secreted and cell surface (csTNF-alpha) forms by activated monocytic and T cells. In this report, we demonstrate that csTNF-alpha may predominantly regulate the human immunodeficiency virus type 1 (HIV-1) long terminal repeat (LTR) activation in the promonocytic cell line U937 and in the Epstein-Barr virus-transformed B-cell line BH1. Anti-TNF-alpha antibody suppressed both the constitutive expression of the HIV-1 LTR in BH1 cells and the expression induced by phorbol 12-myristate 13-acetate in U937 cells. This suppression was found to be mediated via csTNF-alpha. No correlation between the HIV-1 LTR activation and the secretion of TNF-alpha was evident in these cell lines. Suppression of TNF-alpha secretion by cyclosporin A or by a serine protease inhibitor did not suppress the HIV-1 LTR activation. These observations suggest a novel biological role for csTNF-alpha in the immunopathogenesis of AIDS.
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PMID:Transactivation of human immunodeficiency virus type 1 long terminal repeats by cell surface tumor necrosis factor alpha. 194 42

An intragenic enhancer in the pol gene of human immunodeficiency virus type 1 has previously been identified (Verdin et al., Proc. Natl. Acad. Sci. USA 87:4874-4878, 1990). This element is composed of two subdomains both exhibiting phorbol ester-inducible enhancing activity on the viral thymidine kinase promoter in HeLa cells. Examination of the nucleotide sequence of one of these domains (nucleotides 4079 to 4342, HXB2 isolate) revealed the presence of three short DNA regions highly homologous to the recognition site for cellular transcription factor AP-1. Two short oligonucleotides containing these AP-1 sites each functioned as a phorbol ester-inducible enhancer when cloned upstream of the thymidine kinase promoter and transfected into HeLa cells. Gel mobility shift assays and competition experiments using the same two oligonucleotides demonstrated that they bound affinity-purified AP-1 or AP-1 present in uninduced and 12-O-tetradecanoylphorbol-13-acetate-induced HeLa nuclear extracts. Footprinting experiments confirmed that all three predicted sites bound purified AP-1. These results suggest that the AP-1 factor could play a role in the transcriptional regulation of human immunodeficiency virus type 1 gene expression.
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PMID:The intragenic enhancer of human immunodeficiency virus type 1 contains functional AP-1 binding sites. 194 59


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