Exosomes from HIV-1-infected Cells Stimulate Production of Pro-inflammatory Cytokines through Trans-activating Response (TAR) RNA

Tick-borne encephalitis (TBE), a disease caused by tick-borne encephalitis virus (TBEV), represents the most important flaviviral neural infection in Europe and north-eastern Asia. In the central nervous system (CNS), neurons are the primary target for TBEV infection; however, infection of non-neuronal CNS cells, such as astrocytes, is not well understood. In this study, we investigated the interaction between TBEV and primary human astrocytes. We report for the first time, to the best of our knowledge, that primary human astrocytes are sensitive to TBEV infection, although the infection did not affect their viability. The infection induced a marked increase in the expression of glial fibrillary acidic protein, a marker of astrocyte activation. In addition, expression of matrix metalloproteinase 9 and several key pro-inflammatory cytokines/chemokines (e.g. tumour necrosis factor α, interferon α, interleukin (IL)-1β, IL-6, IL-8, interferon γ-induced protein 10, macrophage inflammatory protein, but not monocyte chemotactic protein 1) was upregulated. Moreover, we present a detailed description of morphological changes in TBEV-infected cells, as investigated using three-dimensional electron tomography. Several novel ultrastructural changes were observed, including the formation of unique tubule-like structures of 17.9 ±0.15 nm diameter with associated viral particles and/or virus-induced vesicles and located in the rough endoplasmic reticulum of the TBEV-infected cells. This is the first demonstration that TBEV infection activates primary human astrocytes. The infected astrocytes might be a potential source of pro-inflammatory cytokines in the TBEV-infected brain, and might contribute to the TBEV-induced neurotoxicity and blood–brain barrier breakdown that occurs during TBE. The neuropathological significance of our observations is also discussed.

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Exosomal packaging of trans-activation response element (TAR) RNA by HIV-1 infected cells: a pro-malignancy message delivery to cancer cells

Molecular Biology Reports ◽

10.1007/s11033-019-04770-2 ◽

2019 ◽

Vol 46 (3) ◽

pp. 3607-3612 ◽

Cited By ~ 1

Author(s):

Nilesh Kumar Sharma

Keyword(s):

Cancer Cells ◽

Message Delivery ◽

Response Element ◽

Infected Cells ◽

Activation Response ◽

Tar Rna ◽

Hiv 1

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Down Regulation Of IL-1β Secretion By Tgf-β1 In Macrophages Infected With Dengue Virus

10.1101/2021.02.03.429556 ◽

2021 ◽

Author(s):

Brenda Ramírez-Aguero ◽

Javier Serrato-Salas ◽

José Luis Montiel-Hernández ◽

Judith González-Christen

Keyword(s):

Immune Response ◽

Dengue Virus ◽

Inflammatory Cytokines ◽

Denv Infection ◽

Inhibitory Effect ◽

Microvascular Endothelium ◽

Infected Cells ◽

Tgf Β1 ◽

Pro Inflammatory Cytokines

AbstractSeveral pathogenic mechanisms have been linked to the severity of dengue virus infection, like viral cytotoxicity, underlying host genetics and comorbidities such as diabetes and dyslipidemia. It has been observed that patients with severe manifestations develop an uncontrolled immune response, with an increase in pro-inflammatory cytokines such as TNF, IL-1β, IL-8, IL-6 and chemokines that damage the human microvascular endothelium, and also in anti-inflammatory cytokines IL-4, IL-10 and TGF-β1. The role of TGF-β1 on dengue is not clear; few studies have been published, and most of them from patient sera data, with both protective and pathological roles have described. The aim of this study was to evaluate the ability of TGF-β1 to regulate the secretion of IL-1β in macrophages infected by DENV using THP-1 cells treated with recombinant TGF-β1 before or after DENV infection. By RT-PCR we did not observe a difference in IL-1β expression between infected cells pretreated with TGF-β1 and those that were not. However, secretion of IL-1β was reduced only in cells stimulated with TGF-β1 before infection, and not in those treated 2 hours post-infection. TGF-β1 receptor blockage with SB505124 inhibitor, prior to the addition of TGF-β1 and infection, abrogated the inhibitory effect of TGF-β1. Our results suggest that DENV could regulate the function of TGF-β1 on macrophages. This negative regulation of the TGF-β1 pathway could be used by DENV to evade the immune response and could contribute to the immunopathology.

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Faculty Opinions recommendation of Exosomes derived from HIV-1-infected cells promote growth and progression of cancer via HIV TAR RNA.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.734353972.793554536 ◽

2018 ◽

Author(s):

Santosh Kumar

Keyword(s):

Infected Cells ◽

Tar Rna ◽

Hiv 1

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Histone deacetylase inhibition reduces deleterious cytokine release induced by ingenol stimulation

10.1101/193946 ◽

2017 ◽

Author(s):

Erin T. Larragoite ◽

Laura J. Martins ◽

Adam M. Spivak ◽

Racheal A. Nell ◽

Vicente Planelles

Keyword(s):

Histone Deacetylase ◽

Inflammatory Cytokines ◽

Inflammatory Cytokine ◽

Cytokine Production ◽

Ex Vivo ◽

Viral Reactivation ◽

Inflammatory Cytokine Production ◽

Epigenetic Modifier ◽

Hiv 1 ◽

Pro Inflammatory Cytokines

AbstractIntroductionThough antiretroviral therapy has led to viral suppression and increased quality of life for patients living with HIV-1, strategies to eliminate the HIV-1 latent reservoir are still necessary to eliminate HIV. Latency reversal with superior latency reversal agents (LRAs) such as protein kinase C (PKC) agonists is a promising strategy for unveiling and eliminating the latent HIV-1 reservoir. However, PKC agonists induce T cell activation and deleterious pro- inflammatory cytokine production. Secondary pharmacological agents combined with LRAs have been previously shown to reduce deleterious pro-inflammatory cytokine secretion without inhibiting HIV-1 viral reactivation. Histone deacetylase inhibitors (HDACi) are also known for inhibiting deleterious pro-inflammatory cytokines in the context of graft-versus-host disease and rheumatoid arthritis in addition to being known to synergize with PKC agonists. In this study we investigated whether HDACi and other epigenetic modifiers could decrease PKC- induced pro-inflammatory cytokines secretion while simultaneously synergizing with the PKC agonists Ingenol-3,20-dibenzoate, to enhance latency reversal.MethodsWe screened an epigenetic modifier library in health donor human peripheral blood mononuclear cells (PBMCs) to identify compounds (‘hits’) that reduced intracellular IL-6 pro-inflammatory cytokine production induced by PKC agonist Ingenol-3,20-dibenzoate. We then further tested reducers of intracellular IL-6 (‘hits’) for their ability to synergize with Ingenol-3,20-dibenzoate in the J-LAT 10.6 model of HIV-1 latency. The most promising epigenetic modifier from both screens, the HDACi Panobinostat, was then further tested for its ability to reduce pro-inflammatory cytokines and synergize with Ingenol-3,20-dibenzoate.ResultsWe show that co-treatment with Ingenol-3,20-dibenzoate and Panobinostat reduces pro-inflammatory cytokines and enhances latency reversal in vitro. Panobinostat suppressed pro-inflammatory cytokine production when combined with Ingenol-3,20- dibenzoate ex vivo when using aviremic patient cells, but antagonized Ingenol-3,20-dibenzoate dependent latency reversal ex vivo.ConclusionThe combination of Panobinostat and Ingenol-3,20-dibenzoate reduces deleterious cytokine production but is not a suitable latency reversal combination therapy.

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Identification of Novel Inhibitors of Human Immunodeficiency Virus Type 1 Replication byIn SilicoScreening Targeting Cyclin T1/Tat Interaction

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01711-12 ◽

2012 ◽

Vol 57 (3) ◽

pp. 1323-1331 ◽

Cited By ~ 13

Author(s):

Takayuki Hamasaki ◽

Mika Okamoto ◽

Masanori Baba

Keyword(s):

Human Immunodeficiency Virus ◽

Human Immunodeficiency Virus Type ◽

Virus Type ◽

In Silico ◽

Cyclin T1 ◽

Immunodeficiency Virus ◽

Infected Cells ◽

Tar Rna ◽

Hiv 1

ABSTRACTHuman immunodeficiency virus type 1 (HIV-1) transcription is essential for viral replication and the only step for viral genome amplification. Cyclin T1 (CycT1) interacts with HIV-1 Tat and transactivation-responsive (TAR) RNA, leading to the activation of viral transcription through the hyperphosphorylation of RNA polymerase II (RNAPII). Thus, the CycT1/Tat/TAR RNA interaction represents a novel target for inhibition of HIV-1 replication. In this study, we conductedin silicoscreening of compounds targeting the CycT1/Tat/TAR RNA complex and found that two structurally related compounds (C1 and C2) had high docking scores for a model of the complex. These compounds proved inhibitory to HIV-1 replication in tumor necrosis factor alpha-stimulated chronically infected cells. In addition, C3, a derivative of C1 and C2, was found to be a more potent inhibitor of HIV-1 replication in chronically infected cells. C3 also inhibited HIV-1 replication in acutely infected cells. The compound could suppress Tat-mediated HIV-1 long terminal repeat-driven gene expression and phosphorylation of RNAPII through inhibition of Tat binding to CycT1. Furthermore, the docking pose of C3 was defined by analyses for itsin silicodocking energy andin vitroantiviral activity, which indicates that C3 interacts with Tat-binding amino acids of CycT1. Thus, a series of compounds described herein are novel inhibitors of HIV-1 transcription through inhibition of CycT1/Tat interaction.

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Progesterone augments cell susceptibility to HIV-1 and HIV-1/HSV-2 co-infections

Journal of Molecular Endocrinology ◽

10.1530/jme-16-0138 ◽

2016 ◽

Vol 57 (3) ◽

pp. 185-199 ◽

Cited By ~ 6

Author(s):

Viswanath Ragupathy ◽

Wang Xue ◽

Ji Tan ◽

Krishnakumar Devadas ◽

Yamei Gao ◽

...

Keyword(s):

Viral Load ◽

Inflammatory Cytokines ◽

Virus Type ◽

Mononuclear Cells ◽

Mobility Shift ◽

Peripheral Blood Mononuclear ◽

Progesterone Treatment ◽

Infected Cells ◽

Hiv 1

In human immunodeficiency virus type 1 (HIV-1)-infected women, oral or injectable progesterone containing contraceptive pills may enhance HIV-1 acquisition in vivo, and the mechanism by which this occurs is not fully understood. In developing countries, Herpes simplex virus type-2 (HSV-2) co-infection has been shown to be a risk for increase of HIV-1 acquisition and, if co-infected women use progesterone pills, infections may increase several fold. In this study, we used an in vitro cell culture system to study the effects of progesterone on HIV-1 replication and to explore the molecular mechanism of progesterone effects on infected cells. In our in vitro model, CEMss cells (lymphoblastoid cell line) were infected with either HIV-1 alone or co-infected with HSV-2. HIV-1 viral load was measured with and without sex hormone treatment. Progesterone-treated cells showed an increase in HIV-1 viral load (1411.2 pg/mL) compared with cells without progesterone treatment (993.1 pg/mL). Increased cell death was noted with HSV-2 co-infection and in progesterone-treated cells. Similar observations were noted in peripheral blood mononuclear cells (PBMC) cells derived from three female donors. Progesterone-treated cells also showed reduced antiviral efficacy. Inflammatory cytokines and associations with biomarkers of disease progression were explored. Progesterone upregulated inflammatory cytokines and chemokines conversely and downregulated anti-apoptotic Bcl-2 expression. Nuclear protein analysis by electrophoretic mobility shift assay showed the association of progesterone with progesterone response element (PRE), which may lead to downregulation of Bcl-2. These data indicate that progesterone treatment enhances HIV-1 replication in infected cells and co-infection with HSV-2 may further fuel this process.

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