The Human Immunodeficiency Virus Type 1 Tat Protein Potentiates Zidovudine-Induced Cellular Toxicity In Transgenic Mice

Prakash, Om; Teng, Steven; Ali, Manzoor; Zhu, Xianzhong; Coleman, Roy; Dabdoub, Roberto; Chambers, Richard; Aw, Tak Yee; Flores, Sonia C.; Joshi, Bharat

doi:10.1006/abbi.1997.0168

Cited by 53 publications

(28 citation statements)

References 37 publications

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“…Due to the primary and secondary infections, HIVϩ individuals tend to have activated respiratory burst of the immune cells, elevated level of pro-oxidative cytokine (24,25), and increased intake of pharmaceutical compounds that either cause oxidative damage (e.g. zidovudine (27)) or require GSH for detoxification (13). These, along with a decrease in overall antioxidant capacity (14,28), will undoubtedly create a higher demand for GSH and, in turn, result in an altered redox poise of cells.…”

Section: Discussionmentioning

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%

“…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%

“…In addition, Tat is sufficient to cause both the enhanced activation of NF-B and the increased susceptibility to apoptosis, observed with HIV (42-44). Tat also enhances drug toxicity in vivo (27). Therefore, Tat may be a viral agent that participates in many of the pathological changes that occur upon HIV infection.…”

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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: Discussionmentioning

confidence: 99%

Section: Human Immunodeficiency Virus (Hiv)mentioning

confidence: 99%

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

confidence: 99%

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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“…Several Tat-transgenic mouse models were generated to study the effects of Tat in HIV-1 neuropathogenesis (31,32). Tat expression in the brain caused failure to thrive, a hunched gesture, tremors, ataxia, slow cognitive and motor movements, seizures, and premature death (32).…”

Section: Hiv-tat Impaired Bbb Permeability In Hbmecsmentioning

confidence: 99%

HIV-1 Tat-Mediated Effects on Focal Adhesion Assembly and Permeability in Brain Microvascular Endothelial Cells

Avraham

Jiang

Lee

et al. 2004

The Journal of Immunology

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The blood-brain barrier (BBB) is a network formed mainly by brain microvascular endothelial cells (BMECs). The integrity of the BBB is critical for brain function. Breakdown of the BBB is commonly seen in AIDS patients with HIV-1-associated dementia despite the lack of productive HIV infection of the brain endothelium. The processes by which HIV causes these pathological conditions are not well understood. In this study we characterized the molecular mechanisms by which Tat mediates its pathogenic effects in vitro on primary human BMECs (HBMECs). Tat treatment of HBMECs stimulated cytoskeletal organization and increased focal adhesion sites compared with control cells or cells treated with heat-inactivated Tat. Pretreatment with Tat Abs or with the specific inhibitor SU-1498, which interferes with vascular endothelial growth factor receptor type 2 (Flk-1/KDR) phosphorylation, blocked the ability of Tat to stimulate focal adhesion assembly and the migration of HBMECs. Focal adhesion kinase (FAK) was tyrosine-phosphorylated by Tat and was found to be an important component of focal adhesion sites. Inhibition of FAK by the dominant interfering mutant form, FAK-related nonkinase, significantly blocked HBMEC migration and disrupted focal adhesions upon Tat activation. Furthermore, HIV-Tat induced permeability changes in HBMECs in a time-dependent manner. Tat also impaired BBB permeability, as observed in HIV-1 Tat transgenic mice. These studies define a mechanism for HIV-1 Tat in focal adhesion complex assembly in HBMECs via activation of FAK, leading to cytoskeletal reorganization and permeability changes.

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The Human Immunodeficiency Virus-1 Tat Protein Increases Cell Proliferation, Alters Sensitivity to Zinc Chelator-Induced Apoptosis, and Changes Sp1 DNA Binding in HeLa Cells

Sève

Favier

Osman

et al. 1999

Archives of Biochemistry and Biophysics

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The Human Immunodeficiency Virus Type 1 Tat Protein Potentiates Zidovudine-Induced Cellular Toxicity In Transgenic Mice

Cited by 53 publications

References 37 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 Tat-Mediated Effects on Focal Adhesion Assembly and Permeability in Brain Microvascular Endothelial Cells

The Human Immunodeficiency Virus-1 Tat Protein Increases Cell Proliferation, Alters Sensitivity to Zinc Chelator-Induced Apoptosis, and Changes Sp1 DNA Binding in HeLa Cells

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