HIV-1 Tat-Mediated Apoptosis in Human Brain Microvascular Endothelial Cells

Kim, Tae-Aug; Avraham, Hava; Koh, Young‐Sang; Jiang, Shuxian; Park, In-Woo; Avraham, Shalom

doi:10.4049/jimmunol.170.5.2629

Cited by 99 publications

(81 citation statements)

References 80 publications

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“…Similarly, a lower level of VEGFR-3 activation by fibronectin as compared with VEGF-C was observed in prior studies (35,36). Likewise, modest stimulation of receptor tyrosine kinases by other viral proteins, as compared with their natural ligands, has been observed in T cells and endothelial cells (52)(53)(54). However, a significantly enhanced association of VEGFR-3 and ␣ 3 was observed in cells stimulated with gB (Fig.…”

Section: The Gb-induced Activation Of Vegfr-3 Is Inhibited By Blockinmentioning

confidence: 50%

Kaposi's Sarcoma-associated Herpesvirus Activation of Vascular Endothelial Growth Factor Receptor 3 Alters Endothelial Function and Enhances Infection

Zhang¹,

Wang²,

Chandran

et al. 2005

Journal of Biological Chemistry

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Kaposi's sarcoma-associated herpesvirus (KSHV; also known as human herpesvirus 8) is the etiologic agent of Kaposi's sarcoma, an endothelial neoplasm. This ␥-herpesvirus encodes for several unique proteins that alter target cell function, including the virion envelope-associated glycoprotein B (gB). Glycoprotein B has an RGD (Arg-Gly-Asp) motif at the extracellular amino terminus region and binds to the ␣ 3 ␤ 1 surface integrin, which enhances virus entry. We now report that gB can activate the vascular endothelial growth factor receptor 3 (VEGFR-3) on the surface of microvascular endothelial cells and trigger receptor signaling, which can modulate endothelial migration and proliferation. Furthermore, we observed that VEGFR-3 expression and activation enhance KSHV infection and participate in KSHV-mediated transformation. These functional changes in the endothelium may contribute to the pathogenesis of Kaposi's sarcoma and suggest that interventions that inhibit gB activation of VEGFR-3 could be useful in the treatment of this neoplasm.

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Section: The Gb-induced Activation Of Vegfr-3 Is Inhibited By Blockinmentioning

confidence: 50%

Kaposi's Sarcoma-associated Herpesvirus Activation of Vascular Endothelial Growth Factor Receptor 3 Alters Endothelial Function and Enhances Infection

Zhang¹,

Wang²,

Chandran

et al. 2005

Journal of Biological Chemistry

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“…First, the suppression of T cell proliferation could be due to Tat since it is known to play an important role in T cell apoptosis (32,33). The second possibility could be active suppression of the host-protective T cell response due to production of the counteractive disease promoting cytokines such as IL-10 and IL-4.…”

Section: Il-10 Produced By the Splenocytes Mediate The Suppressor Funmentioning

confidence: 99%

HIV-1 Tat Suppresses gp120-Specific T Cell Response in IL-10-Dependent Manner

Gupta

Boppana

Mishra

et al. 2008

The Journal of Immunology

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A large number of multicomponent vaccine candidates are currently in clinical evaluation, many of which also include the HIV-1 Tat protein, an important regulatory protein of the virus. However, whether Tat, a known immune effector molecule with a well-conserved sequence among different HIV subtypes, affects the immune response to a coimmunogen is not well understood. In this study, using a bicistronic vector expressing both gp120 and Tat, we have analyzed the role of Tat in elicitation of the gp120-specific immune response. The T cell responses to gp120 were greatly diminished in mice coimmunized with Tat as compared with mice immunized with gp120 alone. This immunosuppressive activity of Tat was not confined to viral Ag only because it also suppressed the immune response of unrelated Ag. Analysis of the cytokine profile suggests that Tat induces IL-10 and since IL-10 has been demonstrated to have appreciable T cell inhibitory activity, it is plausible that IL-10 could be responsible for Tat-mediated immunosuppression. Finally, the immunosuppressive effect of Tat was not observed in IL-10-deficient mice, confirming the role of IL-10 in Tat-mediated immunosuppression. Thus, our results demonstrate for the first time that the immunosuppressive effect of Tat is mediated through IL-10 and suggests that Tat-induced IL-10-mediated immune suppression seems to cripple immune surveillance during HIV-1 infection.

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“…For studies of brain endothelial cells we used SV-40-transformed HBMEC; HBMEC were chosen because they have been found to express features of blood-brain barrier endothelial cells and their interaction with bacterial and viral pathogens have been studied extensively (12,(21)(22)(23)(24)(25). HBMEC passages 3-5 were cultured in RPMI 1640 medium (Sigma-Aldrich), supplemented with 10% NuSerum (BD Biosciences, Mountain View, CA), 10% FBS (Sigma-Aldrich), MEM vitamins (BioWhittaker), MEM nonessential amino acids (Sigma-Aldrich), 1 mM sodium pyruvate (BioWhittaker), 2 mM L-glutamine (Sigma-Aldrich), 30 mg/ml endothelial growth supplement (Sigma-Aldrich), and 5 U/ml heparin (Sigma-Aldrich) at 37˚C in 5% CO 2 as described previously (12).…”

Section: Eukaryotic Cellsmentioning

confidence: 99%

IL-10 Prevents Apoptosis of Brain Endothelium during Bacteremia

Londoño

Carvajal

Strle

et al. 2011

The Journal of Immunology

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IL‐10 deficient mice infected with the relapsing fever bacterium Borrelia turicatae rapidly succumb to brain hemorrhage if they are unable to clear peak bacteremia. Here we investigated the protective role of IL‐10 during relapsing‐remitting bacterial infection and explored the molecular events involved in protection of brain endothelium by IL‐10. The results showed that severe endothelial cell injury leading to hemorrhage in the brain and other organs occurred in IL‐10 deficient mice during relapsing‐remitting infection. Human brain microvascular endothelial cells (HBMEC) upon exposure to whole bacteria or purified bacterial lipoprotein are rapidly killed by apoptosis and produced abundant pro‐inflammatory mediators but did not produce any IL‐10. HBMEC apoptosis during exposure to low number of bacteria was associated with down regulation of TNF and TNFAIP3 and upregulation of BAX. In contrast, exposure to high concentrations of purified outer membrane lipoprotein was associated with dramatic upregulation of FAS, FAS ligand, and the adaptor molecules RIPK1 and CFLAR. Exogenous IL‐10 reversed all the apoptotic signaling changes induced by whole bacteria or purified lipoprotein. The results indicate that IL‐10 prevent brain endothelial cell injury and point to a prominent role for bacterial lipoprotein mediated activation of different apoptosis pathways in this process.

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HIV-1 Tat-Mediated Apoptosis in Human Brain Microvascular Endothelial Cells

Cited by 99 publications

References 80 publications

Kaposi's Sarcoma-associated Herpesvirus Activation of Vascular Endothelial Growth Factor Receptor 3 Alters Endothelial Function and Enhances Infection

Kaposi's Sarcoma-associated Herpesvirus Activation of Vascular Endothelial Growth Factor Receptor 3 Alters Endothelial Function and Enhances Infection

HIV-1 Tat Suppresses gp120-Specific T Cell Response in IL-10-Dependent Manner

IL-10 Prevents Apoptosis of Brain Endothelium during Bacteremia

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