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)

The mechanisms of cell death in CD4+ T cells mediated by human herpesvirus 6 (HHV-6) were investigated. The frequency of cell death in the human CD4+ T-cell line JJHAN, which had been inoculated with HHV-6 variant A or B, appeared to be augmented by tumor necrosis factor alpha (TNF-alpha). Agarose gel electrophoresis of DNA from HHV-6-inoculated cells showed DNA fragmentation in multiples of the oligonucleosome length unit. The degree of DNA fragmentation increased when HHV-6-inoculated cells were cultured in the presence of TNF-alpha. Flow cytometry and Scatchard analysis of TNF receptors revealed an increase in the number of the p55 form of TNF receptors on JJHAN cells after HHV-6 inoculation. It also appeared that treatment with anti-Fas monoclonal antibody (MAb) induced marked apoptosis in HHV-6-inoculated cells. Transmission electron microscopy showed characteristics of apoptosis, such as chromatin condensation and fragmentation of nuclei, but virus particles were hardly detected in apoptotic cells. Two-color flow cytometric analysis using anti-HHV-6 MAb and propidium iodide revealed that DNA fragmentation was present predominantly in uninfected cells but not in productively HHV-6-infected cells. In addition, JJHAN cells incubated with UV light-irradiated and ultracentrifuged culture supernatant of HHV-6-infected cells appeared to undergo apoptosis. The present study demonstrated that both HHV-6 variants A and B induce apoptosis in CD4+ T cells by indirect mechanisms, as reported recently in human immunodeficiency virus type 1 infection.
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PMID:Induction of T-cell apoptosis by human herpesvirus 6. 909 50

IL-2 was initially defined as a T lymphocyte growth factor, but recent studies have provided evidence that it may also play a role in regulating T cell differentiation, apoptosis, and tolerance. To examine the contribution of IL-2 to these processes, we have bred a class II-restricted TCR transgene into mice deficient in the alpha-chain of the IL-2R, CD25. We show that in response to Ag, T cells from these mice are unable to use IL-2 and, as a result, are less efficient at traversing the cell cycle, and proliferate less than wild-type cells. Furthermore, CD25 -/- T cells exhibit reduced survival in vitro, even in the presence of costimulatory signals. IL-4 and IL-15, a cytokine related to IL-2, enhance the survival and Ag-induced proliferation of CD25 -/- T cells. Activated CD25 -/- T cells are resistant to Fas-mediated activation-induced cell death (AICD), and this defect cannot be corrected by other cytokines. Therefore, IL-2 plays a unique role in regulating AICD, but has redundant roles in T cell survival and proliferation in vitro. The failure of AICD observed with CD25 -/- T cells may explain the unexpected observation that deficiency of IL-2 or of the alpha- or beta-chain of the IL-2R results not in immunodeficiency, but in autoimmune disease.
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PMID:Functional responses and apoptosis of CD25 (IL-2R alpha)-deficient T cells expressing a transgenic antigen receptor. 910 38

Fas/APO-1 mediates apoptosis via Fas and Fas ligand transduction. Recently, a soluble form of Fas (sFas) was described which seems to be functionally implicated in the Fas signal system, suggesting a relationship between some disorders and sFas function. We measured sFas-levels in sera from normal controls and patients with disorders linked to human retroviral infection of human immunodeficiency virus (HIV) and human T-cell leukemia virus type-1 (HTLV-1). The sFas level of normal controls. HTLV-1 carriers seronegative for HIV, and patients with HTLV-1 associated myelopathy/tropical paraparesis (HAM/TSP), adult T-cell leukemia (ATL), and AIDS was 1.62 +/- 0.49, 1.90 +/- 0.49, 2.00 +/- 0.59, 3.32 +/- 2.05, and 3.06 +/- 0.92 ng/ml, respectively. Although the level of sFas in patient groups with HAM/TSP, ATL, and AIDS was significantly high in comparison to that of normal controls (p < 0.01), the individual values were highly variable within the groups. The sFas level was statistically correlated to the soluble interleukin-2 receptor (sIL-2R) level, as well as to cells expressing membrane Fas (mFas), indicating the same cellular origin. In some ATL cases, however, serum sFas levels and mFas expression density on leukemic T-cells were discrepant, with especially high levels of the soluble form and a lack of expression of the membrane form observed in 2 cases, sFas detection could serve as a putative marker for active diseases in patients with ATL and AIDS.
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PMID:Serum levels of soluble Fas/APO-1 receptor in human retroviral infection and associated diseases. 914 6

Apoptosis is postulated to be involved as an anti-viral immune mechanism by killing infected cells before viral replication has occurred. The Fas-Fas ligand interaction is a powerful regulator of T cell apoptosis and could potentially act as a potent anti-viral immune mechanism against T cell tropic virus such as human immunodeficiency virus (HIV). We investigated the status of Fas ligand in peripheral blood mononuclear cells (PBMCs) obtained from persons infected with HIV. We found that monocytes in freshly isolated PBMCs from healthy individuals possess cell surface Fas ligand. In contrast, monocytes in freshly isolated PBMCs from HIV-infected patients had no detectable Fas ligand on the cell surface. Consistent with these findings of surface expression, Fas ligand activity was deficient in the cells from HIV-infected persons. The effect of replacing Fas ligand activity on HIV production by patients' cells was assessed in an in vitro assay. The addition of a functional anti-Fas antibody to PBMCs from HIV-infected individuals inhibited viral production by greater than 90% without affecting lymphocytic function. These findings suggest the possibility of a new therapeutic modality for the treatment of HIV-infected individuals based on the reconstitution of Fas ligand activity.
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PMID:Fas ligand deficiency in HIV disease. 915 65

We have previously demonstrated that CD4 cross-linking (CD4XL) results in apoptosis of CD4+ T cells and augmentation of Fas antigen (CD95, APO-1) expression in CD4+ and CD8+ T cells. Here we demonstrate that CD4XL mediated by both, anti-CD4 monoclonal antibody (MoAb) or human immunodeficiency virus (HIV) envelope protein gp120 reduces the expression of the proto-oncogene Bcl-2 in CD4+ T cells, but not in CD8+ T cells, concurrently with the induction of CD4+ T cell-apoptosis. Additionally, the Bcl-2dim population expressed high levels of Fas antigen. Bax, an antagonist of Bcl-2, was brightly expressed even in the Bcl-2dim population. Addition of interleukin (IL)-2 rescued CD4+ T cells from CD4XL-induced Bcl-2 downmodulation and apoptosis induction. These results support the hypothesis that CD4 ligation by HIV-1 envelope protein in vivo in HIV-infected patients selectively reduces Bcl-2 protein in CD4+ T lymphocytes, thereby facilitating Fas/Fas-ligand triggered apoptosis; furthermore the findings reported expand the rationale for use of IL-2 in HIV disease.
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PMID:Modulation of Bcl-2 protein by CD4 cross-linking: a possible mechanism for lymphocyte apoptosis in human immunodeficiency virus infection and for rescue of apoptosis by interleukin-2. 922 75

Apoptosis of peripheral blood T cells has been suggested to play an important role in the pathogenesis of human immunodeficiency virus (HIV) infection. Spontaneous, Fas (CD95)-induced and activation-induced T cell apoptosis have all been described in peripheral blood mononuclear cell cultures of HIV-infected individuals. We have previously shown that activation-induced T cell apoptosis is Fas independent in peripheral blood T cells from HIV+ individuals. In this study, we extend and confirm these observations by using an inhibitor of interleukin-1 beta converting enzyme (ICE) homologues. We show that z-VAD-fmk, a tripeptide inhibitor of ICE homologues, can inhibit Fas-induced apoptosis of peripheral blood CD4(+) and CD8+ T cells from asymptomatic HIV+ individuals. z-VAD-fmk also inhibited activation (anti-CD3)- induced CD4+ and CD8+ T cell apoptosis (AICD) in some but not all asymptomatic HIV+ individuals. Apoptosis was measured by multiparameter flow cytometry. The z-VAD-fmk inhibitor also enhanced survival of T cells in anti-Fas or anti-CD3 antibody-treated cultures and inhibited DNA fragmentation. AICD that could be inhibited by z-VAD-fmk was Fas independent and could be inhibited with a blocking monoclonal antibody to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), a recently described member of the TNF/nerve growth factor ligand family. The above findings show that Fas-induced T cell apoptosis is ICE dependent in HIV infection. AICD can be blocked by ICE inhibitors in some patients, and this AICD is mediated by TRAIL. These results show that TRAIL can be a mediator of AICD in T cells. These different mechanisms of peripheral blood T cell apoptosis may play different roles in the pathogenesis of HIV infection.
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PMID:Interleukin-1 beta converting enzyme-like protease involvement in Fas-induced and activation-induced peripheral blood T cell apoptosis in HIV infection. TNF-related apoptosis-inducing ligand can mediate activation-induced T cell death in HIV infection. 933 76

We have investigated the relative contribution of apoptosis or programmed cell death (PCD) to cell killing during acute infection with T-cell-tropic, cytopathic human immunodeficiency virus type 1 (HIV-1), by employing diverse strategies to inhibit PCD or to detect its common end-stage sequelae. When Bcl-2-transfected cell lines were infected with HIV-1, their viability was only slightly higher than that of control infections. Although the adenovirus E1B 19-kDa protein has been reported to be a stronger competitor of apoptosis than Bcl-2, it did not inhibit HIV-mediated cell death better than Bcl-2 protein. Competition for Fas ligand or inactivation of the Fas pathway secondary to intracellular mutation (MOLT-4 T cells) also had modest effects on overall cell death during acute HIV infection. In contrast to these observations with HIV infection or with HIV envelope-initiated cell death, Tat-expressing cell lines were much more susceptible (200% enhancement) to Fas-induced apoptosis than controls and Bcl-2 overexpression strongly (75%) inhibited this apoptotic T-cell death. PCD associated with FasR ligation resulted in the cleavage of common interleukin-1beta-converting enzyme (ICE)-protease targets, poly(ADP-ribose) polymerase (PARP) and pro-ICE, whereas cleaved products were not readily detected during HIV infection of peripheral blood mononuclear cells or T-cell lines even during periods of extensive cell death. These results indicate that one important form of HIV-mediated cell killing proceeds by a pathway that lacks the characteristics of T-cell apoptosis. Our observations support the conclusion that at least two HIV genes (env and tat) can kill T cells by distinct pathways and that an envelope-initiated process of T-cell death can be discriminated from apoptosis by many of the properties most closely associated with apoptotic cell death.
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PMID:A major human immunodeficiency virus type 1-initiated killing pathway distinct from apoptosis. 937 41

We examined the relationships among CD4+-T-cell counts, spontaneous apoptosis, and Fas expression among peripheral blood mononuclear cells obtained from human immunodeficiency virus type 1 (HIV-1)-infected patients. After 2 days of incubation, propidium iodide DNA staining and flow cytometry revealed that peripheral blood mononuclear cells from subjects with the lowest CD4+-cell numbers (0 to 99/microl; n = 20) showed the highest frequency of apoptosis: 22.4% +/- 2.7% (mean +/- standard error) versus 13.8% +/- 1.2% and 12.7% +/- 1.4% among peripheral blood mononuclear cells obtained from patients with 100 to 499 CD4+ cells/microl (n = 19) and >500 CD4+ cells/microl (n = 17), respectively. Each of these means differed significantly from the mean frequency of apoptosis (6.3% +/- 0.7%) of peripheral blood mononuclear cells obtained from HIV-1-seronegative controls (P < 0.001, Student's t test). After incubation, the percentage of peripheral blood mononuclear cells expressing Fas antigen was increased for the HIV-1-infected subjects, and this was most evident for patients with more advanced disease. Among patients with fewer than 100 CD4+ cells/microl, 64.4% +/- 5.4% of peripheral blood mononuclear cells were Fas+, as opposed to 25.8% +/- 3.0% and 14.5% +/- 1.7% Fas+ cells among patients with more than 100 CD4+ cells/microl and healthy controls, respectively (P < 0.05 for each group comparison). Interestingly, in all populations, most apoptotic cells did not express Fas. Thus, apoptosis and Fas expression are increased in incubated peripheral blood mononuclear cells obtained from HIV-1-infected patients and these phenomena are enhanced as disease progresses.
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PMID:CD4+-T-cell counts, spontaneous apoptosis, and Fas expression in peripheral blood mononuclear cells obtained from human immunodeficiency virus type 1-infected subjects. 938

Infection by the human immunodeficiency virus (HIV-1) causes chronic ongoing inflammation in HIV-1 seropositive individuals as shown by high plasma levels of inflammatory cytokines and production of reactive oxygen intermediates (ROIs). One source of ROIs is provided from the very early stages of HIV infection by activated polymorphonuclear neutrophils. Tat, the viral protein, is also specifically responsible for an endogenous cellular increase of ROI. In this review we also evaluate the effects of this oxidative stress on various biological parameters such as immune response and survival of T lymphocytes, virus transcription and replication. It was clearly demonstrated in ex vivo experiments that the oxidative stress due to infection itself participates in CD4+ T lymphocyte depletion by increasing their rate of apoptosis and particularly of Fas-induced apoptosis. This oxidative stress also facilitates NF-kappa B-dependent activation of HIV transcription. In vitro studies suggest that the early steps of HIV activation from its quiescent state might be subsequently facilitated by this oxidative environment. Whereas already active replication is not influenced. The data presented here lead to a better understanding of the consequences of oxidative stress on the pathophysiology of HIV infection and also enable us to evaluate the potential use of antioxidant molecules as therapeutic agents against AIDS.
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PMID:Oxidative stress in human immunodeficiency virus infection. 944 38

CD8+ lymphocytes are believed to be important in host defence against the human immunodeficiency virus (HIV)-1, inhibiting HIV-1 replication through both cytolytic and non-cytolytic pathways. The cytolytic pathway involves calcium-dependent exocytosis of perforin and granzyme proteases, as well as Fas-mediated programmed cell death, whereas the noncytolytic pathway involves the release of chemokines that prevent viral entry. Using granzyme A as a marker of cytolytic granule proteins, and macrophage inflammatory protein (MIP)-1alpha and RANTES as markers of HIV-1 inhibitory chemokines, we show that these two very different mediators of viral inhibition are both localized in the cytolytic granules of HIV-1-specific CD8+ cytotoxic T lymphocytes (CTL). Following antigen-specific activation, these mediators are secreted together, facilitating both lysis of virion-producing cells and the inhibition of free virus. In addition, RANTES, MIP-1alpha and MIP-1beta are secreted by CTL as a macromolecular complex containing sulphated proteoglycans. This association appears to have a functional significance, because heparan sulphate facilitates RANTES inhibition of HIV-1 infection of monocytes.
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PMID:Beta-chemokines are released from HIV-1-specific cytolytic T-cell granules complexed to proteoglycans. 949 45


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