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

A chronically HIV-1-infected T cell clone (J1.1) derived from Jurkat cells was developed that possesses defects in CD3 signaling. This clone was phenotypically determined to be CD4- and express a reduced surface density of CD3 as compared with a pool of uninfected Jurkat clones. Although J1.1 could be induced with TNF-alpha to produce HIV-1 particles, stimulation via the CD3 (T3-Ti) complex, using mAb cross-linking, had no effect on viral production. Further investigation revealed that J1.1 secreted approximately 20-fold less IL-2 than did uninfected Jurkat cells after anti-CD3 treatment. In addition, a separate defect in Ca2+ mobilization was noted in the HIV-1-infected J1.1 line when compared with uninfected Jurkat cells after anti-CD3 cross-linking. The cell line described offers a new model in which to study the mechanisms of several defects directly imposed by HIV-1 on CD3+ cells.
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PMID:An HIV-1-infected T cell clone defective in IL-2 production and Ca2+ mobilization after CD3 stimulation. 183 65

Cytopathic viruses injure cells by a number of different mechanisms. The mechanism by which HIV-1 injures T cells was studied by temporally examining host-cell macromolecular syntheses, stages of the cell cycle, and membrane permeability following acute infection. T cells cytopathically infected at an m.o.i. of 1-5 grew normally for 24-72 hr, depending on the cell line, followed by the first manifestation of cell injury, slowing of cell division. At that time significant amounts of unintegrated HIV DNA and p24 core protein became detectable, and acridine orange flow cytometric cell cycle studies demonstrated the presence of fewer cells in the G2/M stage of the cell cycle. There was no change in the frequency of cells in the S-stage, and metabolic pulsing with radioactive precursors demonstrated that host-cell DNA, RNA, and protein syntheses were normal at that time and normal up to the time cells started to die (approximately 24 hr later), when all three decreased. Cellular lipid synthesis, however, was perturbed when cell multiplication slowed, with phospholipid synthesis reduced and neutral lipid synthesis enhanced. Permeability of the host-cell membrane to small molecules, such as Ca2+ and sucrose, was slightly enhanced early postinfection, and by the time of slowing of cell division, host membrane permeability was greatly increased to both Ca2+ and sucrose (Stokes radius 5.2 A) but not to inulin (Stokes radium 20 A). These changes in host-cell membrane permeability and phospholipid synthesis were not observed in acutely infected H9 cells, which are not susceptible to HIV cytopathology. Thus, HIV-1 appeared to predominantly injure T cells by perturbing host-cell membrane permeability and lipid synthesis, which is similar to the cytopathic mechanisms of paramyxoviruses.
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PMID:Perturbation of host-cell membrane is a primary mechanism of HIV cytopathology. 190 81

Since animal models of human immunodeficiency virus (HIV) infection are being used increasingly in determining various aspects of virus/host interaction and as models for virus expression, it will be important to assess any significant differences in anti-viral immune responses between animals and humans. Previous studies have shown that incubation of HIV with non-immune sera from several animal species results in virus neutralization, and that rabbit serum can lyse HIV-infected cells. The objectives of the current study were to evaluate the animal complement pathway(s) activated by HIV and HIV-infected cells and determine the mechanism by which complement could mediate viral neutralization. Incubation of HIV-infected cells with mouse, guinea-pig or rabbit sera resulted in cell-surface deposition of C3 fragments. Deposition of C3 fragments did not occur either in the presence of C4-deficient guinea-pig serum or in the absence of Ca2+, indicating that activation by infected cells occurred via the classical pathway. Neutralization of free virus was also mediated by the classical pathway since C4-deficient guinea-pig serum and Ca(2+)-chelated sera lacked activity. Serum treatment of virus resulted in release of HIV reverse transcriptase (RT), suggesting that neutralization occurred by C5b-9-mediated virolysis. RT was also released from simian immunodeficiency virus by animal complement. Antibodies in animal sera were not responsible for the classical pathway activation by free virus or HIV-infected cells. These results define several substantial differences between animal and human complement reactivity with HIV which could significantly affect the ability of HIV to replicate in animals, and which need to be considered in the assessment of animal models of HIV infection.
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PMID:Human immunodeficiency virus (HIV)-infected cells and free virus directly activate the classical complement pathway in rabbit, mouse and guinea-pig sera; activation results in virus neutralization by virolysis. 191 89

The endocrine and metabolic consequences of illicit drug use and HIV disease are extensive and profound. Both narcotic drug use and AIDS have the capacity to cause clinically significant multiglandular derangements. Admittedly, we were not able to focus as much attention on the less frequently occurring disturbances of calcium, phosphorus, or folate metabolism in HIV disease. Similarly, we reported very little information about the endocrinologic significance of the use of classes of narcotics other than opiates and to a far lesser extent cocaine. Even with these limitations, the spectrum of drug abuse and HIV-related endocrine manifestations discussed previously is quite diverse. Given the pervasive effects of drug abuse on other organ systems, it is not surprising to find expanding interest in the endocrine consequences of narcotic drug use. In fact, the use of these drugs is responsible, in part, for the past and continuing interest in identifying receptors for these agents and similarly structured endogenous ligands. As these investigations proceed, we must appreciate the limitations in translating basic and clinical scientific findings to the clinical setting. Much of the current research does not study street-relevant narcotic doses, does not use research designs involving polydrug use, and does not involve the processes or routes of drug administration used by active narcotic addicts. There is a critical need for more research methods with animal models and clinical study settings that more adequately mimic drug use outside of the laboratory. Our ability to develop appropriate psychopharmaceutical agents to respond to the different faces of drug abuse in the United States will depend on continued progress in the area of neuroendocrinology. With respect to the consequences of HIV disease, the clinical findings of elevated hormonal levels in some endocrine systems are amazing given what one would expect if one postulated direct or indirect destruction by HIV or the opportunistic complications that accompany AIDS. In unraveling this puzzle, careful attention must be given to evaluating the degree to which the clinical or biochemical consequences are due to a direct HIV effect, to an effect of a complicating infection or neoplasm, or to an AIDS-related therapeutic intervention. More work is needed also in obtaining histopathologic information to correlate with the biochemical and clinical derangement. In summary, there is a wealth of information demonstrating a wide spectrum of endocrine/metabolic consequences of drug abuse and AIDS. Still, just as many questions remain unanswered. While the exact biologic mechanisms are unclear, many of the biochemical aberrations have clinical relevance.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Endocrine complications of AIDS and drug addiction. 193 23

We investigated mechanisms by which the soluble native envelope glycoprotein gp120 of the human immunodeficiency virus (HIV-1) suppresses antigen-driven T cell responses. For this study, exogenous interleukin-2 (IL-2)-independent, antigen-specific, CD4 positive, human T-cell clones were developed by cyclic restimulation with soluble tetanus toxoid antigen. In the presence of soluble antigen and antigen-presenting cells (APC), T-cell clones proliferated and secreted IL-2. Purified gp120 suppressed the proliferative responses of the T-cell clones with concomitant suppression of IL-2 secretion; proliferative responses of CD8+ T cells preincubated with gp120 were not inhibited. A short pulse of 20 minutes with gp120 was sufficient to inhibit the proliferative response of the T-cell clones. Anti-CD3 monoclonal antibody (MoAb)-driven proliferation of the T-cell clones was also suppressed by gp120, but responses elicited by mitogens, phorbol myristate acetate (PMA) plus calcium ionophore, ionomycin, anti-CD2 MoAbs, and a combination of anti-CD3 plus anti-CD28 MoAb driven responses remained unaffected. Investigation of signal transduction events showed that antigen-driven early activation signals via translocation of protein kinase C (PKC), increase in intracellular inositol phosphates, and increase in intracellular calcium were suppressed in gp120 pretreated, tetanus toxoid antigen-stimulated T-cell clones. One mechanism of immune suppression by gp120 may involve interference with the initiation of signal transduction through the T-cell receptor complex.
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PMID:Inhibition of functional properties of tetanus antigen-specific T-cell clones by envelope glycoprotein GP120 of human immunodeficiency virus. 196 13

Infection with HIV causes a reduction in the numbers and function of CD4+ lymphocytes and functional abnormalities of other cells. We have studied the effect of HIV infection on signal transduction in the H9 lymphoblastoid CD4+ cell line. Resting HIV-infected H9 cells show evidence of chronic activation with raised levels of InsP3 and InsP4, the active metabolites of the inositol polyphosphate pathway, and a consequently raised intracellular free calcium concentration. Stimulation of HIV-infected H9 cells with phytohemagglutinin (PHA) leads to a fall in the previously raised levels of InsP3 but a further rise in InsP4, whilst an attenuated intracellular calcium rise is seen with both PHA and anti-CD3 antibody. The observed effects of HIV infection on signal transduction provide a mechanism to explain the functional defects in CD4+ lymphocytes and, possibly, other cell types.
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PMID:HIV infection of H9 lymphoblastoid cells chronically activates the inositol polyphosphate pathway. 196 81

Mechanisms accounting for HIV-associated suppression of lymphocyte proliferation were investigated. In previous work we demonstrated that purified and inactivated HIV-suppressed lymphoid cell proliferation. In this report we used an inactivated preparation of HIV obtained from infected CEM cells grown in serum free media and demonstrated that this HIV-associated suppression acted in the early steps of activation to inhibit the incorporation of radiolabeled phosphorus into phosphatidylinositol 4,5-bisphosphate and phosphatidic acid. Initially we showed that both purified CD4 and CD8 T lymphocyte subsets were affected and HIV-associated inhibition did not require the CD4 molecule. Impaired lymphocyte blastogenesis (decreased size and granularity and decreased expression of receptors to IL-2 and transferrin) in response to PHA indicated an effect of inactivated HIV on the early steps of activation. This was confirmed by time studies where 1) a 2 min HIV-pretreatment followed by washing before stimulation was sufficient to inhibit PHA induced proliferation of normal lymphocytes, and 2) addition of HIV to PHA prestimulated lymphocytes failed to inhibit proliferation, e.g., there was no effect on preactivated lymphocytes. HIV was mainly inhibitory of lymphocyte proliferation induced by PHA or mAb to the CD3 receptor. In contrast to the effect on the CD3/TiR, responses via the CD2 receptor were not suppressed, e.g., stimulation with the monoclonal antibodies T11(2) + T11(3). Inasmuch as responses by direct A23187 + PMA stimulation of intracellular pathways were also inhibited, it appears that the HIV-induced defect was not (or not only) membrane receptor mediated. The earliest (min) measurable event after stimulation was the initial increase in intracellular Ca2+ which was unaffected by HIV pretreatment. The next measurable event (min to h) of stimulation is a sustained increase in inositol phospholipid turnover. Pretreatment of mononuclear cells with inactivated HIV resulted in a decreased inositol phospholipid turnover as judged from decreased 32P incorporation into phosphatidylinositol 4-phosphate and phosphatidylinositol 4,5-bisphosphate. This led to decreased generation of DAG as reflected in the reduced radiolabeling of its metabolite PA. Reduced availability of DAG presumably interferes with pkC activation and leads to decreased expression of receptors for IL-2 and transferrin and impaired proliferation.
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PMID:HIV inhibits the early steps of lymphocyte activation, including initiation of inositol phospholipid metabolism. 197 48

The interference of the recombinant HIV-1 glycoproteins gp160 and gp120 with the CD3/T cell antigen receptor (TcR)-mediated activation process has been investigated in the CD4+ diphtheria toxoid-specific human P28D T cell clone. Both glycoproteins clearly inhibit the T cell proliferation induced in an antigen-presenting cell (APC)-free system by various cross-linked monoclonal antibodies specific for the CD3 molecule or the TcR alpha chain (up to 80% inhibition). Biochemical studies further demonstrate that exposure of the T cell clone to both glycoproteins (gps) specifically inhibits the CD3/TcR phospholipase C (PLC) transduction pathway, without affecting the CD3/TcR cell surface expression. Thus, inositol phosphate production, phosphatidic acid turnover, intracellular free calcium, and intracellular pH increase induced by CD3/TcR-specific MAbs are specifically impaired in gps-treated P28D T cells. Addition of purified soluble CD4 prevents binding of gps to T cells and overcomes all observed inhibitions. Maximal inhibitions are obtained for long-term exposure of the T cell clone to gps (16 h). No early effect of gps is observed. By contrast, gp160 and gp120 fail to suppress the CD2-triggered functional and biochemical P28D T cell responses. These results demonstrate that, in addition to their postulated role in the alteration of the interaction between CD4 on T lymphocytes and MHC class II molecules on APC, soluble HIV-1 envelope glycoproteins may directly and specifically impair the CD3/TcR-mediated activation of PLC in uninfected T cells via the CD4 molecule.
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PMID:Human immunodeficiency virus-1 glycoproteins gp120 and gp160 specifically inhibit the CD3/T cell-antigen receptor phosphoinositide transduction pathway. 197 39

The highly glycosylated envelope glycoprotein (gp 160) of human immunodeficiency virus (HIV) interacts with the CD4 molecule present on the membrane of CD4+ cells and is involved in the pathobiology of HIV infection. Lectins bind glycoproteins through non-covalent interactions with specific hexose residues. The mammalian C-type lectin bovine conglutinin was examined for its ability to interact with recombinant gp160 (rgp160) produced in vaccinia virus-infected BHK21 cells. Specific binding of conglutinin to rgp160 was demonstrated by ELISA. The interaction of bovine conglutinin with rgp160 was calcium-dependent, which is characteristic of the binding of a C-type lectin to its ligand, and the binding was inhibited in a dose-dependent manner with N-acetyl-D-glucosamine. Deglycosylation of rgp160 abrogated the conglutinin binding. In addition, conglutinin exerted a dose-dependent inhibition of the binding of rgp160 to the CD4 receptor on CEM 13 cells, as demonstrated by FACS analyses. These results indicate that conglutinin may inhibit the infection with HIV-1 through its interaction with the viral envelope glycoprotein.
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PMID:Conglutinin binds the HIV-1 envelope glycoprotein gp 160 and inhibits its interaction with cell membrane CD4. 199 9

We have studied the conditions of in vitro binding of platelet glycoprotein IIb/IIIa (GPIIb/IIIa) to fibrinogen and applied the results to identify and measure the serum inhibitors to the binding. For the enzyme-linked immunosorbent assay, platelet extract was delivered to a fibrinogen-coated microtiter plate that was incubated for 2 hours, followed by incubation with anti-GPIIb/IIIa monoclonal antibody for another 2 hours. The plate was then incubated with peroxidase-conjugated anti-mouse IgG for color development. The binding was shown to be calcium-dependent. The binding was partially blocked by treating the coated fibrinogen with anti-fibrinogen antibody. Reduction or dissociation of GPIIb/IIIa resulted in the total loss of its ability to bind to fibrinogen. Platelet extracts of patients with hemophilia showed decreased binding (25% and 14%, compared with control platelet extract), and an extract from a patient with Glanzmann's thrombasthenia showed no binding. With the enzyme-linked immunosorbent assay we have measured serum inhibitors to GPIIb/IIIa binding to fibrinogen in 35 hemophilia A, 17 immune thrombocytopenic purpura, 22 human immunodeficiency virus-related immune thrombocytopenic purpura, and 29 systemic lupus erythematosus serum samples. In those patients with inhibition by serum, polyethylene glycol precipitation of circulating immune complexes (CICs) decreased the inhibition by the supernatants, and all the resolubilized CIC precipitates demonstrated inhibition, which indicates that CICs play a major role in the inhibition of GPIIb/IIIa binding to fibrinogen. This, then, provides evidence of CIC-mediated impaired GPIIb/IIIa binding to fibrinogen in hemophilia A, HIV-ITP, and SLE.
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PMID:Inhibition of platelet GPIIb/IIIa binding to fibrinogen by serum factors: studies of circulating immune complexes and platelet antibodies in patients with hemophilia, immune thrombocytopenic purpura, human immunodeficiency virus-related immune thrombocytopenic purpura, and systemic lupus erythematosus. 200 77


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