Tat protein of human immunodeficiency virus type 1 represses expression of manganese superoxide dismutase in HeLa cells.

Flores, Sonia C.; Marecki, John C.; Harper, K.; Bose, S. K.; Nelson, Sally K.; McCord, Joe M.

doi:10.1073/pnas.90.16.7632

Cited by 198 publications

(141 citation statements)

References 54 publications

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“…A 10 -40% decrease in GSH content can completely inhibit lymphocyte activation in vitro (8). Indeed, the very fact that Tat modulates GSH biosynthesis in addition to suppressing the activity of manganese superoxide dismutase (27,41,42) may testify to the importance of redox regulation in HIV pathogenesis. Specifically, these prooxidative effects of Tat may enhance its NF-B-dependent transactivating potential (6,7,42,43), suggesting that the effect of Tat on the GSH status is a specific and self-promoting event in HIV pathology.…”

Section: Fig 3 Gcs-ls Protein Content Is Decreased In Liver and Erymentioning

confidence: 99%

“…Tat is associated with AIDS-related dementia (38) as well as two of the most frequent cancers associated with AIDS: Kaposi's sarcoma (39) and B cell lymphoma (40). Tat has been shown to lower total and reduced GSH concentration in vitro in various cell lines and also the total sulfhydryl content in vivo in a transgenic animal model (27,41,42). In addition, Tat is sufficient to cause both the enhanced activation of NF-B and the increased susceptibility to apoptosis, observed with HIV (42)(43)(44).…”

Section: Human Immunodeficiency Virus (Hiv)mentioning

confidence: 99%

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Molecular Mechanism of Decreased Glutathione Content in Human Immunodeficiency Virus Type 1 Tat-transgenic Mice

Choi¹,

Liu²,

Kundu³

et al. 2000

Journal of Biological Chemistry

153

105

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Human immunodeficiency virus (HIV) progressively depletes GSH content in humans.Although the accumulated evidence suggests a role of decreased GSH in the pathogenesis of HIV, significant controversy remains concerning the mechanism of GSH depletion, especially in regard to envisioning appropriate therapeutic strategies to help compensate for such decreased antioxidant capacity. Tat, a transactivator encoded by HIV, is sufficient to cause GSH depletion in vitro and is implicated in AIDS-associated Kaposi's sarcoma and B cell lymphoma. In this study, we report a decrease in GSH biosynthesis with Tat, using HIV-1 Tat transgenic (Tat؉) mice. A significant decline in the total intracellular GSH content in liver and erythrocytes of Tat؉ mice was accompanied by decreased ␥-glutamylcysteine synthetase regulatory subunit mRNA and protein content, which resulted in an increased sensitivity of ␥-glutamylcysteine synthetase to feedback inhibition by GSH. Further study revealed a significant reduction in the activity of GSH synthetase in liver of Tat؉ mice, which was linearly associated with their GSH content. Therefore, Tat appears to decrease GSH in vivo, at least partially, through modulation of GSH biosynthetic enzymes. Human immunodeficiency virus (HIV)1 infection is associated with a systemic decrease in the GSH content in humans (1, 2). Such biochemical alteration appears to be a direct consequence of retroviral infection rather than a late and indirect consequence of advanced disease state, is progressive in nature, and often occurs in the absence of any symptoms associated with AIDS (2-5). The importance of this decreased GSH is suggested by the fact that decreased GSH can enhance HIV expression via activation of NF-B (4, 6, 7) and contribute to diverse immune dysfunctions found in AIDS, including the loss of CD4ϩ T lymphocytes via apoptosis (8 -11). In fact, such decline in the GSH content may play a role in the increased drug toxicity and oxidative damage, often found in HIV-infected individuals (12-15). Furthermore, increased GSH or other sulfhydryl compounds can inhibit viral replication (7, 16), HIV-1 reverse transcriptase activity (16,17), and the late stage of viral expression (18). GSH content may even predict the survival of HIV-seropositive (HIVϩ) individuals (19,20). Therefore, it is perhaps crucial to determine whether this decrease in GSH occurs through an accelerated loss of GSH or specific modulation of its synthesis, especially as it relates to potential therapeutic strategies to compensate for such decreased antioxidant capacity. However, despite over a decade of intensive research on this subject, the exact mechanism(s) causing decreased GSH content with HIV remains unclear.Cells maintain their high GSH content in part by reducing GSSG back to GSH, preventing the loss of GSH as GSSG (12). Also, GSH is synthesized from its amino acid constituents via two consecutive reactions catalyzed by ␥-glutamylcysteine synthetase (GCS; glutamate-cysteine ligase, EC 6.3.2.2) and GSH synthetase (GS; EC6.3.2.3). I...

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Section: Fig 3 Gcs-ls Protein Content Is Decreased In Liver and Erymentioning

confidence: 99%

Section: Human Immunodeficiency Virus (Hiv)mentioning

confidence: 99%

Molecular Mechanism of Decreased Glutathione Content in Human Immunodeficiency Virus Type 1 Tat-transgenic Mice

Choi¹,

Liu²,

Kundu³

et al. 2000

Journal of Biological Chemistry

153

105

View full text Add to dashboard Cite

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“…It has been reported that HIV-1 Tat by itself does not activate NF-B, but rather potentiates the TNF-␣-mediated activation of NF-B (Westendorp et al, 1995). This potentiation was due to a change in the redox state of the cells caused by down-regulation of magnesium superoxide dismutase (Mn-SOD) expression (Flores et al, 1993;Westendorp et al, 1995). In contrast to Tat, gp120 is unable to inhibit activity and expression of Mn-SOD, but it can amplify TNF-␣-induced NF-B-binding activity in CD4-positive Jurkat T cells (Shatrov et al, 1996).…”

mentioning

confidence: 99%

HIV-1 Envelope Glycoprotein 120 Increases Intercellular Adhesion Molecule-1 Expression by Human Endothelial Cells

Ren

Yao

Chen

2002

Laboratory Investigation

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SUMMARY:Human immunodeficiency virus type 1 (HIV-1) infection is often associated with central nervous system damage and vascular complications. However, the mechanisms of this association are largely unknown. We examined the effect of HIV-1 envelope glycoprotein 120 (gp120) on cell adhesion molecule expression by endothelial cells. We found, for the first time, that both soluble and membrane-bound gp120 could significantly increase the expression of human endothelial intercellular adhesion molecule-1 (ICAM-1) at both mRNA and protein levels, but not vascular cell adhesion molecule-1 and E-selectin. The specificity of gp120-mediated response was demonstrated by blocking experiments using a specific monoclonal antibody against gp120, which successfully abolished the gp120-mediated increase of ICAM-1 expression. Furthermore, there was a significant increase of human monocytic cell line THP-1 adherence onto the gp120-treated endothelial monolayers. This increased cell adhesion was effectively blocked by either anti-gp120 or anti-ICAM antibodies. These findings suggest that HIV-1 gp120-mediated endothelial ICAM-1 expression could be one of the important mechanisms of HIV-1 pathogenesis. (Lab Invest 2002, 82:245-255). B oth human immunodeficiency virus (HIV)-positiveand acquired immune deficiency syndrome (AIDS) patients often have significantly increased levels of circulating cell adhesion molecules, such as intercellular adhesion molecule-1 (ICAM-1) and vascular adhesion molecule-1 (VCAM-1) (Greenwood et al, 1998; Seigneur et al, 1997). Serum ICAM-1 levels correlate well with AIDS progression in HIV type 1 (HIV-1)-infected patients (Galea et al, 1997). Endothelial cells and leukocytes from these patients exhibit a significant increase of such adhesion molecules (Pillet et al, 1999;Zietz et al, 1996). HIV-1 particles also incorporate many cell adhesion molecules (Guo and Hildreth, 1995). HIV-associated ICAM-1 is biologically active and can enhance virus infectivity (Fortin et al, 1997) and virus-induced syncytium formation (Gruber et al, 1991). ICAM-1-bearing viruses are less susceptible to neutralization by anti-envelope glycoprotein 120 (gp120) monoclonal antibodies than the same virus produced in cells expressing no ICAM-1 (Sawyer et al, 1994). HIV-1 replication in monocytes/macrophages is significantly enhanced by interaction with endothelial cells through cell adhesion molecules (Gilles et al, 1995). In addition, alterations in expression of cell adhesion molecules by leukocytes and endothelial cells can increase leukocyte migration into the tissues, which may result in certain organ damage. Indeed, HIV-1-infected leukocytes can transmigrate into the central nervous system and cause encephalopathy (Nottet, 1999). Endothelial cell dysfunction and leukocyte infiltration may also be attributable to the increased frequency of vascular complications such as atherosclerosis in HIV-1-infected patients (Constans et al, 1995;Tabib et al, 2000).Several factors may contribute to the increased levels of cell adhesion mole...

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“…Microglia exposed to Tat induce nitric-oxide synthase and NO production, and this induction is also dependent upon NF-B (26). On the other hand, negative effects include repression of major histocompatibility class-I gene promoter activity (27) and of the important antioxidant enzyme maganese-superoxide dismutase (28). Interestingly, a deregulation of cytokine expression and/or secretion is a hallmark of HIV infection (29 -32).…”

mentioning

confidence: 99%

The Human Immunodeficiency Virus-1 Tat Protein Activates Human Umbilical Vein Endothelial Cell E-selectin Expression via an NF-κB-dependent Mechanism

Cota‐Gomez¹,

Flores²,

Cruz³

et al. 2002

Journal of Biological Chemistry

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Tat protein of human immunodeficiency virus type 1 represses expression of manganese superoxide dismutase in HeLa cells.

Cited by 198 publications

References 54 publications

Molecular Mechanism of Decreased Glutathione Content in Human Immunodeficiency Virus Type 1 Tat-transgenic Mice

Molecular Mechanism of Decreased Glutathione Content in Human Immunodeficiency Virus Type 1 Tat-transgenic Mice

HIV-1 Envelope Glycoprotein 120 Increases Intercellular Adhesion Molecule-1 Expression by Human Endothelial Cells

The Human Immunodeficiency Virus-1 Tat Protein Activates Human Umbilical Vein Endothelial Cell E-selectin Expression via an NF-κB-dependent Mechanism

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