Effect of the redox state on HIV-1 tat protein multimerization and cell internalization and trafficking

Pierleoni, Raffaella; Menotta, Michele; Antonelli, A.; Sfara, Carla; Serafini, Giordano; Dominici, Sabrina; Laguardia, Maria Elena; Salis, Annalisa; Damonte, Gianluca; Banci, Lucia; Porcu, Marco; Monini, Paolo; Ensoli, Barbara; Magnani, Mauro

doi:10.1007/s11010-010-0564-9

Cited by 16 publications

(14 citation statements)

References 44 publications

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“…There seemed to be two coexistent populations, one of small oligomers and the other, more disperse, of large aggregates. Even though the monomers and dimers were more frequent than larger aggregates (for example, the sample presented here showed eleven monomers and only four 50-mers) less than 10% of the sample was in monomeric form (Figure 2b inset ), and therefore functionally active 31 . Evaluation of the Tat secondary structure in PBS at pH 7.4 by CD was done for Tat samples at 0.1 µM, 1 µM, 10 µM, 20 µM.…”

Section: Resultsmentioning

confidence: 86%

“…The spherical shape allows Tat to assume the least possible volume, at the lowest free energy state. The oligomerized state is believed to be functionally inactive 31 . This would suggest that Tat may be nearly 10 fold more potent as a neurotoxin than suggested by the in vitro assays 35,36 .…”

Section: Discussionmentioning

confidence: 99%

“…In contrast, we found that Tat, a small peptide, increased aggregation of Aβ and at the same time, dramatically increased degeneration and neuronal death. Tat protein loses its neurotoxic potential rapidly by aggregation and oxidation 31 . However, in the presence of Aβ peptide even after seven days at room temperature under atmospheric conditions the toxicity of Aβ-Tat aggregates were enhanced, as compared with Aβ only.…”

Section: Discussionmentioning

confidence: 99%

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HIV Tat protein and amyloid-β peptide form multifibrillar structures that cause neurotoxicity

Hategan

Bianchet²,

Steiner

et al. 2017

Nat Struct Mol Biol

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We investigated direct interactions between the human immunodeficiency virus (HIV)-trans-activator of transcription (Tat) protein and amyloid β peptide. Amyloid β-Tat complexes are readily formed extracellularly in the brain. In vitro studies showed that in the presence of Tat, the uniform amyloid fibrils turned into double twisted fibrils followed by populations with thick unstructured filaments and aggregated large patches in a dose-dependent manner. The fibers became more rigid and mechanically resistant. Tat attached externally to fibrils, causing their lateral aggregation into thick multifibrilar structures. These present growth in β sheet and enhanced adhesion. The neurotoxic properties of Tat and amyloid β aggregates were strongly synergistic when complexed together in vitro and in animal models. These data suggest that the increased rigidity and mechanical resistance of the amyloid β-Tat complexes coupled with stronger adhesion due to the presence of Tat in the fibrils accounted for the increased damage, likely through pore formation in membranes.

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Section: Resultsmentioning

confidence: 86%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

HIV Tat protein and amyloid-β peptide form multifibrillar structures that cause neurotoxicity

Hategan

Bianchet²,

Steiner

et al. 2017

Nat Struct Mol Biol

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“…It has recently been demonstrated that the redox state of HIV-Tat affects its biological activity [39]. In particular, the Tat protein enters the cell and its reduced isoform reaches the cytoplasm and nucleus whereas its oxidized form tends to form multi-aggregates that are less toxic in infected cells.…”

Section: Discussionmentioning

confidence: 99%

The HIV-1 Transactivator Factor (Tat) Induces Enterocyte Apoptosis through a Redox-Mediated Mechanism

et al. 2011

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The intestinal mucosa is an important target of human immunodeficiency virus (HIV) infection. HIV virus induces CD4+ T cell loss and epithelial damage which results in increased intestinal permeability. The mechanisms involved in nutrient malabsorption and alterations of intestinal mucosal architecture are unknown. We previously demonstrated that HIV-1 transactivator factor (Tat) induces an enterotoxic effect on intestinal epithelial cells that could be responsible for HIV-associated diarrhea. Since oxidative stress is implicated in the pathogenesis and morbidity of HIV infection, we evaluated whether Tat induces apoptosis of human enterocytes through oxidative stress, and whether the antioxidant N-acetylcysteine (NAC) could prevent it. Caco-2 and HT29 cells or human intestinal mucosa specimens were exposed to Tat alone or combined with NAC. In an in-vitro cell model, Tat increased the generation of reactive oxygen species and decreased antioxidant defenses as judged by a reduction in catalase activity and a reduced (GSH)/oxidized (GSSG) glutathione ratio. Tat also induced cytochrome c release from mitochondria to cytosol, and caspase-3 activation. Rectal dialysis samples from HIV-infected patients were positive for the oxidative stress marker 8-hydroxy-2′-deoxyguanosine. GSH/GSSG imbalance and apoptosis occurred in jejunal specimens from HIV-positive patients at baseline and from HIV-negative specimens exposed to Tat. Experiments with neutralizing anti-Tat antibodies showed that these effects were direct and specific. Pre-treatment with NAC prevented Tat-induced apoptosis and restored the glutathione balance in both the in-vitro and the ex-vivo model. These findings indicate that oxidative stress is one of the mechanism involved in HIV-intestinal disease.

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“…Recombinant proteins were induced with isopropyl β-D-thio-galactopyranoside (IPTG) and purified as described in the AIDS Reagent Program protocol, with an added second purification step. Proteins were subjected to a 30 kDa filtration (Millipore) to retain only the active monomeric form of Tat [59]. Proteins were then solubilized in acidic phosphate buffer (pH ≈ 4) to maintain cysteine residues in a reduce form important for Tat activity [60].…”

Section: Methodsmentioning

confidence: 99%

Didehydro-Cortistatin A Inhibits HIV-1 Tat Mediated Neuroinflammation and Prevents Potentiation of Cocaine Reward in Tat Transgenic Mice

Mediouni¹,

Jablonski²,

Paris³

et al. 2015

CHR

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HIV-1 Tat protein has been shown to have a crucial role in HIV-1-associated neurocognitive disorders (HAND), which includes a group of syndromes ranging from undetectable neurocognitive impairment to dementia. The abuse of psychostimulants, such as cocaine, by HIV infected individuals, may accelerate and intensify neurological damage. On the other hand, exposure to Tat potentiates cocaine-mediated reward mechanisms, which further promotes HAND. Here, we show that didehydro-Cortistatin A (dCA), an analog of a natural steroidal alkaloid, crosses the blood-brain barrier, cross-neutralizes Tat activity from several HIV-1 clades and decreases Tat uptake by glial cell lines. In addition, dCA potently inhibits Tat mediated dysregulation of IL-1β, TNF-α and MCP-1, key neuroinflammatory signaling proteins. Importantly, using a mouse model where doxycycline induces Tat expression, we demonstrate that dCA reverses the potentiation of cocaine-mediated reward. Our results suggest that adding a Tat inhibitor, such as dCA, to current antiretroviral therapy may reduce HIV-1-related neuropathogenesis.

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Effect of the redox state on HIV-1 tat protein multimerization and cell internalization and trafficking

Cited by 16 publications

References 44 publications

HIV Tat protein and amyloid-β peptide form multifibrillar structures that cause neurotoxicity

HIV Tat protein and amyloid-β peptide form multifibrillar structures that cause neurotoxicity

The HIV-1 Transactivator Factor (Tat) Induces Enterocyte Apoptosis through a Redox-Mediated Mechanism

Didehydro-Cortistatin A Inhibits HIV-1 Tat Mediated Neuroinflammation and Prevents Potentiation of Cocaine Reward in Tat Transgenic Mice

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