Fibroblast Growth Factor-2 and the HIV-1 Tat Protein Synergize in Promoting Bcl-2 Expression and Preventing Endothelial Cell Apoptosis: Implications for the Pathogenesis of AIDS-Associated Kaposi's Sarcoma

Sgadari, Cecilia; Barillari, Giovanni; Palladino, Clelia; Bellino, Stefania; Taddeo, Brunella; Toschi, Elena; Ensoli, Barbara

doi:10.1155/2011/452729

Cited by 11 publications

(9 citation statements)

References 39 publications

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“…In addition, we noted a reduced number of renal epithelial cells undergoing apoptosis in 7-day-old HIV-Tg 26 mice infected with rAd- Tat vectors compared to the controls. It is tempting to speculate that Tat, in combination with bFGF-2 and VEGF-A, might have an anti-apoptotic effect ( Sgadari et al, 2011 ), as both heparin-binding growth factors were upregulated at this time point. However, as shown in children with HIVAN, apoptotic changes were also detected in dilated renal tubules of 35-day-old HIV-Tg 26 mice infected with rAd- Tat vectors.…”

Section: Discussionmentioning

confidence: 99%

An HIV-Tat inducible mouse model system of childhood HIV-associated nephropathy

Tang

Das

et al. 2020

Disease Models &Amp; Mechanisms

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Background: Modern antiretroviral therapies (ART) have decreased the prevalence of HIV-associated nephropathy (HIVAN). Nonetheless, we continue to see children and adolescents with HIVAN all over the world. Furthermore, once HIVAN is established in children, it is difficult to revert its long-term progression, and we need better animal models of childhood HIVAN to test new treatments.Objectives. To define whether the HIV-1 trans-activator (Tat) gene precipitates HIVAN in young mice, and to develop an inducible mouse model of childhood HIVAN.Design/Methods: An HIV-Tat gene cloned from a child with HIVAN was used to generate recombinant adenoviral vectors (rAd-Tat). rAd-Tat and LacZ control vectors (2 x 109) were expressed in the kidney of newborn wild type and HIV-transgenic (Tg26) FVB/N mice without significant proteinuria (n=5 - 8 per group). Mice were sacrificed 7 and 35 days later to assess their renal outcome, the expression of HIV-genes and growth factors, and markers of cell growth and differentiation by RT-qPCR, immunohistochemistry, and/or Western blots.Results: HIV-Tat induced the expression of HIV-1 genes (env) and heparin binding growth factors in the kidney of HIV-Tg26 mice, and precipitated HIVAN in the first month of life. No significant renal changes were detected in wild type mice infected with rAd-Tat vectors, suggesting that HIV-Tat alone does not induce renal disease.Conclusion. This new mouse model of childhood HIVAN highlights the critical role that HIV-Tat plays in the pathogenesis of HIVAN, and could be used to study the pathogenesis and treatment of HIVAN in children and adolescents.

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Section: Discussionmentioning

confidence: 99%

An HIV-Tat inducible mouse model system of childhood HIV-associated nephropathy

Tang

Das

et al. 2020

Disease Models &Amp; Mechanisms

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“…HHIP target genes FGF-2 [45] and ATF5 [27] positively regulate expression of Bcl-2 anti-apoptotic protein, which showed decreased expression accompanied by increased pro-apoptotic protein Bax expression in cigarette smoke (CS) induced cell death in vitro [46] and in vivo [47]. Additionally, BIRC5, a potent anti-apoptosis protein, interferes with cell death through caspase-dependent and independent mechanisms [48].…”

Section: Discussionmentioning

confidence: 99%

Gene expression analysis uncovers novel hedgehog interacting protein (HHIP) effects in human bronchial epithelial cells

et al. 2013

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Hedgehog Interacting Protein (HHIP) was implicated in chronic obstructive pulmonary disease (COPD) by genome-wide association studies (GWAS). However, it remains unclear how HHIP contributes to COPD pathogenesis. To identify genes regulated by HHIP, we performed gene expression microarray analysis in a human bronchial epithelial cell line (Beas-2B) stably infected with HHIP shRNAs. HHIP silencing led to differential expression of 296 genes; enrichment for variants nominally associated with COPD was found. Eighteen of the differentially expressed genes were validated by real-time PCR in Beas-2B cells. Seven of 11 validated genes tested in human COPD and control lung tissues demonstrated significant gene expression differences. Functional annotation indicated enrichment for extracellular matrix and cell growth genes. Network modeling demonstrated that the extracellular matrix and cell proliferation genes influenced by HHIP tended to be interconnected. Thus, we identified potential HHIP targets in human bronchial epithelial cells that may contribute to COPD pathogenesis.

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“…An increased survival of effectors T cells during the contraction phase has been attributed to the interaction among CD80 or CD86 expressed on DCs with CD28 expressed on the T cells [ 73 ], to Bcl-2 expression [ 55 ] and to IL-2 co-stimulation [ 73 , 74 ]. As Tat is known to induce DC activation and expression of CD80 and CD86 [ 15 , 16 ], to directly enhance CD28 co-stimulation [ 6 ], to up-regulate Bcl-2 expression [ 18 , 75 ] and to promote IL-2 secretion [ 6 , 17 , 76 , 77 ], it is tempting to speculate that these different Tat-mediated mechanisms are involved in the delayed contraction phase occurring in Tat-treated mice. Moreover, as IL-2 favors the generation of CD62L low effector memory cells [ 78 ], Tat-mediated IL-2 secretion can account for the accumulation of effector memory CD8 + T cells observed in Tat-treated mice ( Figure 5 ).…”

Section: Discussionmentioning

confidence: 99%

The HIV-1 Tat Protein Induces the Activation of CD8+ T Cells and Affects In Vivo the Magnitude and Kinetics of Antiviral Responses

et al. 2013

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T cells are functionally compromised during HIV infection despite their increased activation and proliferation. Although T cell hyperactivation is one of the best predictive markers for disease progression, its causes are poorly understood. Anti-tat natural immunity as well as anti-tat antibodies induced by Tat immunization protect from progression to AIDS and reverse signs of immune activation in HIV-infected patients suggesting a role of Tat in T cell dysfunctionality. The Tat protein of HIV-1 is known to induce, in vitro, the activation of CD4+ T lymphocytes, but its role on CD8+ T cells and how these effects modulate, in vivo, the immune response to pathogens are not known. To characterize the role of Tat in T cell hyperactivation and dysfunction, we examined the effect of Tat on CD8+ T cell responses and antiviral immunity in different ex vivo and in vivo models of antigenic stimulation, including HSV infection. We demonstrate for the first time that the presence of Tat during priming of CD8+ T cells favors the activation of antigen-specific CTLs. Effector CD8+ T cells generated in the presence of Tat undergo an enhanced and prolonged expansion that turns to a partial dysfunctionality at the peak of the response, and worsens HSV acute infection. Moreover, Tat favors the development of effector memory CD8+ T cells and a transient loss of B cells, two hallmarks of the chronic immune activation observed in HIV-infected patients. Our data provide evidence that Tat affects CD8+ T cell responses to co-pathogens and suggest that Tat may contribute to the CD8+ T cell hyperactivation observed in HIV-infected individuals.

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Fibroblast Growth Factor-2 and the HIV-1 Tat Protein Synergize in Promoting Bcl-2 Expression and Preventing Endothelial Cell Apoptosis: Implications for the Pathogenesis of AIDS-Associated Kaposi's Sarcoma

Cited by 11 publications

References 39 publications

An HIV-Tat inducible mouse model system of childhood HIV-associated nephropathy

An HIV-Tat inducible mouse model system of childhood HIV-associated nephropathy

Gene expression analysis uncovers novel hedgehog interacting protein (HHIP) effects in human bronchial epithelial cells

The HIV-1 Tat Protein Induces the Activation of CD8+ T Cells and Affects In Vivo the Magnitude and Kinetics of Antiviral Responses

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