HIV-1 Tat increases the adhesion of monocytes and T-cells to the endothelium in vitro and in vivo: implications for AIDS-associated vasculopathy

Matzen, K; Dirkx, Anita E. M.; Egbrink, Mirjam G.A. oude; Speth, Cornelia; Götte, Matthias; Ascherl, Gudrun; Grimm, Thomas W.; Griffioen, Arjan W.; Stürzl, Michael

doi:10.1016/j.virusres.2004.04.001

Cited by 35 publications

(34 citation statements)

References 47 publications

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“…The concentration of recombinant Tat (100 nM) used in the present studies is consistent with those used in our previous in vitro studies (33) and with similar studies from other laboratories (57,60,61). These concentrations are considerably higher than the estimated physiological concentration of Tat in the tissues or body fluids from HIV-1-infected individuals (62).…”

Section: Discussionsupporting

confidence: 89%

Functional Synergy between CD40 Ligand and HIV-1 Tat Contributes to Inflammation: Implications in HIV Type 1 Dementia

Sui

Sniderhan

Schifitto³

et al. 2007

The Journal of Immunology

113

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HIV type 1 (HIV-1)-associated dementia (HAD) is believed to occur due to aberrant activation of monocyte-derived macrophages and brain-resident microglial cells by viral proteins as well as by the proinflammatory mediators released by infected cells. To investigate the inflammatory aspects of the disease, we examined the levels of soluble CD40L (sCD40L) in paired samples of plasma and cerebrospinal fluid obtained from 25 HIV-infected individuals. A significantly higher level of sCD40L was detected in both cerebrospinal fluid and plasma from HIV-infected patients with cognitive impairment, compared with their nonimpaired counterparts. The contribution of sCD40L to the pathogenesis of HAD was then examined by in vitro experiments. rCD40L synergized with HIV-1 Tat to increase TNF-α release from primary human monocytes and microglia, in an NF-κB-dependent manner. The mechanistic basis for this synergism was attributed to a Tat-mediated up-regulation of CD40 in monocytes and microglia. Finally, the CD40L-mediated increase in TNF-α production by monocytes was shown to be biologically important; immunodepletion experiments revealed that TNF-α was essential for the neurotoxic effects of conditioned medium recovered from Tat/CD40L-treated monocytes. Taken together, our results show that CD40 signaling in microglia and monocytes can synergize with the effects of Tat, further amplifying inflammatory processes within the CNS and influencing neuronal survival.

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Section: Discussionsupporting

confidence: 89%

Functional Synergy between CD40 Ligand and HIV-1 Tat Contributes to Inflammation: Implications in HIV Type 1 Dementia

Sui

Sniderhan

Schifitto³

et al. 2007

The Journal of Immunology

113

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“…These effects, in turn, contribute to the pathogenesis of lymphomas, AIDSdementia, 5 cardiovascular diseases, and atherosclerosis. 6 A decrease in endothelium-dependent vasorelaxation and endothelial nitric oxide synthase expression may also play a role in endothelial dysfunctions mediated by Tat. 7 On these bases, Tat is considered a main target for the development of anti-AIDS therapies, and different anti-Tat strategies have been described, including gene therapies, vaccines, and Tat antagonists.…”

mentioning

confidence: 99%

Integrin α_Vβ₃as a Target for Blocking HIV-1 Tat-Induced Endothelial Cell Activation In Vitro and Angiogenesis In Vivo

Urbinati

Mitola

Tanghetti

et al. 2005

ATVB

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Objective-The transactivating factor (Tat) of HIV-1 binds to ␣ v ␤ 3 integrin present on endothelial cells contributing to neovascularization. Here, we investigated the biological consequences of Tat/␣ v ␤ 3 interaction and the antagonist effect of an Arg-Gly-Asp (RGD)-based peptidomimetic. Methods and Results-Binding of Tat to endothelial ␣ v ␤ 3 triggers focal adhesion kinase and nuclear factor-B activation, leading to endothelial cell proliferation, membrane ruffling, and motility in vitro and neovascularization in vivo. The RGD-peptidomimetic SCH221153 inhibits Tat/␣ v ␤ 3 interaction in a solid phase binding assay and endothelial cell adhesion to immobilized Tat with a potency higher than that of RGD-containing peptides. Accordingly, SCH221153 inhibits Tat/␣ v ␤ 3 -dependent focal adhesion kinase and nuclear factor-B activation, proliferation, membrane ruffling, and motility in endothelial cells. Finally, SCH221153 inhibits the angiogenic response triggered by Tat in the chick-embryo chorioallantoic membrane without affecting physiological vascularization. SCH221153 exerts these inhibitory effects without affecting the interaction of Tat with endothelial heparan sulfate proteoglycans or with the vascular endothelial growth factor receptor-2/kinase domain-containing receptor. In all the assays the negative control SCH216687 was ineffective. Conclusion-These data provide new insights on the mechanism of endothelial cell activation by Tat and point to RGD peptidomimetics as prototypes for the development of novel Tat Key Words: HIV-1 Ⅲ Tat Ⅲ endothelium Ⅲ integrin Ⅲ angiogenesis T at protein, the main transactivating factor of HIV-1, 1 is released by HIV-1-infected cells 2 targeting different types of uninfected cells and causing a variety of biological effects related to distinct AIDS-associated pathologies. In AIDS patients, Tat contributes to tumorigenesis, 2 to the pathogenesis of dementia, 3 to the immune system suppression (by interfering with the function of different cells of immunity), 2 and to heart disease and atherosclerosis. 4 The involvement of endothelial cells (ECs) in Tatdependent pathologies is manifold. 5 By inducing neovascularization, Tat contributes to tumor progression and Kaposi sarcoma (KS) development. 2 Also, Tat increases endothelial permeability and alters the expression of endothelial leukocyte receptors, leading to the extravasation of HIV-1ϩ monocytes and HIV-1 dissemination. These effects, in turn, contribute to the pathogenesis of lymphomas, AIDSdementia, 5 cardiovascular diseases, and atherosclerosis. 6 A decrease in endothelium-dependent vasorelaxation and endothelial nitric oxide synthase expression may also play a role in endothelial dysfunctions mediated by Tat. 7 On these bases, Tat is considered a main target for the development of anti-AIDS therapies, and different anti-Tat strategies have been described, including gene therapies, vaccines, and Tat antagonists. 8 Tat accumulates in the extracellular matrix as an immobilized protein, 9 and substrate-immobilized Tat int...

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“…The tat protein acts synergistically with tumor necrosis factor a to increase adhesion of leukocytes to endothelial cells. 69 Thus, it appears that there are several mechanisms by which HIV infection may promote atherogenesis.…”

Section: Studies Evaluating Surrogate Markers Of Atherosclerosismentioning

confidence: 99%

Dyslipidemia Management in Patients With Human Immunodeficiency Virus

Brett-Major¹,

Ganesan²

2007

Infectious Diseases in Clinical Practice

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Both effective antiretroviral therapy and human immunodeficiency virus (HIV) infection have been associated with changes in serum lipids. Data on the relevance of this dyslipidemia on cardiovascular risk are growing. Although guidelines for managing dyslipidemia in HIV-infected patients are available, consideration of the changing literature is important to develop a stepwise approach for management. In this review, the 2003 guidelines of Infectious Diseases Society of America and HIV Medicine Association on dyslipidemia management of patients on antiretroviral therapy are merged with subsequent literature. (Infect Dis Clin Pract 2007;15:7-16)

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HIV-1 Tat increases the adhesion of monocytes and T-cells to the endothelium in vitro and in vivo: implications for AIDS-associated vasculopathy

Cited by 35 publications

References 47 publications

Functional Synergy between CD40 Ligand and HIV-1 Tat Contributes to Inflammation: Implications in HIV Type 1 Dementia

Functional Synergy between CD40 Ligand and HIV-1 Tat Contributes to Inflammation: Implications in HIV Type 1 Dementia

Integrin α_Vβ₃as a Target for Blocking HIV-1 Tat-Induced Endothelial Cell Activation In Vitro and Angiogenesis In Vivo

Dyslipidemia Management in Patients With Human Immunodeficiency Virus

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HIV-1 Tat increases the adhesion of monocytes and T-cells to the endothelium in vitro and in vivo: implications for AIDS-associated vasculopathy

Cited by 35 publications

References 47 publications

Functional Synergy between CD40 Ligand and HIV-1 Tat Contributes to Inflammation: Implications in HIV Type 1 Dementia

Functional Synergy between CD40 Ligand and HIV-1 Tat Contributes to Inflammation: Implications in HIV Type 1 Dementia

Integrin αVβ3as a Target for Blocking HIV-1 Tat-Induced Endothelial Cell Activation In Vitro and Angiogenesis In Vivo

Dyslipidemia Management in Patients With Human Immunodeficiency Virus

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Integrin α_Vβ₃as a Target for Blocking HIV-1 Tat-Induced Endothelial Cell Activation In Vitro and Angiogenesis In Vivo