scholarly journals HIV-1 Vpr Degrades TET2 to Suppress IRF7 and Interferon Expression in Plasmacytoid Dendritic Cells

2019 ◽  
Author(s):  
Qi Wang ◽  
Li-Chung Tsao ◽  
Lei Lv ◽  
Yanping Xu ◽  
Liang Cheng ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Viral Infections ◽  
Constitutive Expression ◽  
Plasmacytoid Dendritic Cells ◽  
Type I Interferons ◽  
Type I ◽  
Restriction Factors ◽  
Host Restriction ◽  
Host Restriction Factors ◽  
Hiv 1

AbstractPlasmacytoid dendritic cells (pDCs) are the major source of type I interferons (IFN-I) in rapid response to viral infections, with constitutive expression of interferon regulatory factor 7 (IRF7). HIV-1 expresses several accessory proteins to counteract specific IFN-induced host restriction factors. As one abundant virion-associated protein, HIV-1 Vpr remains enigmatic in enhancing HIV-1 infection via unclear mechanisms. Here we report that Vpr impaired IFN-I induction in pDCs to enhance HIV-1 replication in CD4+ T cells. Blockade of IFN-I signaling abrogated the effect of Vpr on HIV-1 replication. Virion-associated Vpr suppressed IFN-I induction in pDC by TLR7 agonists. Modulation of IFN-I induction by Vpr was genetically dependent on its activity of TET2 degradation. We further demonstrate that Vpr-mediated TET2 degradation reduced expression of IRF7 in pDCs. Finally, degradation of TET2 in pDCs by Vpr reduced the demethylation level of the IRF7 promoter via CXXC5-dependent recruitment. We conclude that HIV-1 Vpr functions to promote HIV-1 replication by suppressing TET2-dependent IRF7 expression and IFN-I induction in pDCs. The Vpr-TET2-IRF7 axis provides a novel therapeutic target to control HIV-1 infection.

Host Restriction Factors and Human Immunodeficiency Virus (HIV-1): A Dynamic Interplay Involving All Phases of the Viral Life Cycle

2018 ◽  
Vol 16 (3) ◽  
pp. 184-207 ◽  
Author(s):  
Vanessa D`Urbano ◽  
Elisa De Crignis ◽  
Maria Carla Re
Keyword(s):  
Mammalian Cells ◽  
Viral Evolution ◽  
Type I ◽  
Restriction Factors ◽  
Host Restriction ◽  
Host Restriction Factors ◽  
Immunodeficiency Virus ◽  
Lentiviral Infection ◽  
Specific Proteins ◽  
Hiv 1

Mammalian cells have evolved several mechanisms to prevent or block lentiviral infection and spread. Among the innate immune mechanisms, the signaling cascade triggered by type I interferon (IFN) plays a pivotal role in limiting the burden of HIV-1. In the presence of IFN, human cells upregulate the expression of a number of genes, referred to as IFN-stimulated genes (ISGs), many of them acting as antiviral restriction factors (RFs). RFs are dominant proteins that target different essential steps of the viral cycle, thereby providing an early line of defense against the virus. The identification and characterization of RFs have provided unique insights into the molecular biology of HIV-1, further revealing the complex host-pathogen interplay that characterizes the infection. The presence of RFs drove viral evolution, forcing the virus to develop specific proteins to counteract their activity. The knowledge of the mechanisms that prevent viral infection and their viral counterparts may offer new insights to improve current antiviral strategies. This review provides an overview of the RFs targeting HIV-1 replication and the mechanisms that regulate their expression as well as their impact on viral replication and the clinical course of the disease.

scholarly journals Human plasmacytoid dendritic cells are equipped with antigen-presenting and tumoricidal capacities

Blood ◽  
2012 ◽  
Vol 120 (19) ◽  
pp. 3936-3944 ◽  
Author(s):  
Jurjen Tel ◽  
Evelien L. Smits ◽  
Sébastien Anguille ◽  
Rubin N. Joshi ◽  
Carl G. Figdor ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Viral Infections ◽  
Cell Subset ◽  
Plasmacytoid Dendritic Cells ◽  
Type I Interferons ◽  
Human Interferon ◽  
Target Cells ◽  
Type I ◽  
Dendritic Cell Subset ◽  
Antigen Presenting

Abstract Human plasmacytoid dendritic cells (pDCs) represent a highly specialized naturally occurring dendritic-cell subset and are the main producers of type I interferons (IFNs) in response to viral infections. We show that human pDCs activated by the preventive vaccine FSME specifically up-regulate CD56 on their surface, a marker that was thought to be specific for NK cells and associated with cytolytic effector functions. We observed that FSME-activated pDCs specifically lysed NK target cells and expressed cytotoxic molecules, such as tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and granzyme B. Elevated levels of these molecules coincided with the expression of CD56, indicative for skewing human pDCs toward an interferon-producing killer DC subset. Detailed phenotypical and functional analysis revealed that pDCs attained a mature phenotype, secreted proinflammatory cytokines, and had the capacity to present antigens and stimulate T cells. Here, we report on the generation of CD56+ human interferon producing killer pDCs with the capacity to present antigens. These findings aid in deciphering the role for pDCs in antitumor immunity and present a promising prospect of developing antitumor therapy using pDCs.

scholarly journals Type I Interferon Production of Plasmacytoid Dendritic Cells under Control

2021 ◽  
Vol 22 (8) ◽  
pp. 4190
Author(s):  
Dóra Bencze ◽  
Tünde Fekete ◽  
Kitti Pázmándi
Keyword(s):  
Dendritic Cells ◽  
Viral Infections ◽  
Plasmacytoid Dendritic Cells ◽  
Type I Interferons ◽  
Type I ◽  
Type I Ifn ◽  
Tumor Resistance ◽  
Endogenous Factors ◽  
Associated Diseases ◽  
Type I Ifns

One of the most powerful and multifaceted cytokines produced by immune cells are type I interferons (IFNs), the basal secretion of which contributes to the maintenance of immune homeostasis, while their activation-induced production is essential to effective immune responses. Although, each cell is capable of producing type I IFNs, plasmacytoid dendritic cells (pDCs) possess a unique ability to rapidly produce large amounts of them. Importantly, type I IFNs have a prominent role in the pathomechanism of various pDC-associated diseases. Deficiency in type I IFN production increases the risk of more severe viral infections and the development of certain allergic reactions, and supports tumor resistance; nevertheless, its overproduction promotes autoimmune reactions. Therefore, the tight regulation of type I IFN responses of pDCs is essential to maintain an adequate level of immune response without causing adverse effects. Here, our goal was to summarize those endogenous factors that can influence the type I IFN responses of pDCs, and thus might serve as possible therapeutic targets in pDC-associated diseases. Furthermore, we briefly discuss the current therapeutic approaches targeting the pDC-type I IFN axis in viral infections, cancer, autoimmunity, and allergy, together with their limitations defined by the Janus-faced nature of pDC-derived type I IFNs.

PLASMACYTOID DENDRITIC CELLS FUNCTION IN HIV INFECTION

2008 ◽  
Vol 31 (4) ◽  
pp. 13
Author(s):  
Martin Hyrcza ◽  
Mario Ostrowski ◽  
Sandy Der
Keyword(s):  
Dendritic Cells ◽  
Influenza Virus ◽  
Hiv Infection ◽  
Gene Transcription ◽  
Sendai Virus ◽  
Plasmacytoid Dendritic Cells ◽  
Type I Interferons ◽  
Interferon Response ◽  
Type I ◽  
Type I Ifn

Plasmacytoid dendritic cells (pDCs) are innate immune cells able to produce large quantities of type I interferons (IFN) when activated. Human immunodeficiency virus (HIV)-infected patients show generalized immune dysfunction characterized in part by chronic interferon response. In this study we investigated the role of dendritic cells inactivating and maintaining this response. Specifically we compared the IFN geneactivity in pDCs in response to several viruses and TLR agonists. We hypothesized that 1) the pattern of IFN gene transcription would differ in pDCs treated with HIV than with other agents, and 2) that pDCs from patients from different stages of disease would respond differently to the stimulations. To test these hypotheses, we obtained pDCs from 15 HIV-infected and uninfected individuals and treated freshly isolated pDCs with either HIV (BAL strain), influenza virus (A/PR/8/34), Sendai virus (Cantell strain), TLR7 agonist(imiquimod), or TLR9 agonist (CpG-ODN) for 6h. Type I IFN gene transcription was monitored by real time qPCRfor IFNA1, A2, A5, A6, A8,A17, B1, and E1, and cytokine levels were assayed by Cytometric Bead Arrays forTNF?, IL6, IL8, IL10, IL1?, and IL12p70. pDC function as determined by these two assays showed no difference between HIV-infected and uninfected patients or between patients with early or chronic infection. Specifically, HIV did notinduce type I IFN gene expression, whereas influenza virus, Sendai virus and imiquimod did. Similarly, HIV failed to induce any cytokine release from pDCs in contrast to influenza virus, Sendai virus and imiquimod, which stimulatedrelease of TNF?, IL6, or IL8. Together these results suggest that the reaction of pDCs to HIV virus is quantitatively different from the response to agents such as virus, Sendai virus, and imiquimod. In addition, pDCs from HIV-infected persons have responses similar to pDCs from uninfected donors, suggesting, that the DC function may not be affected by HIV infection.

scholarly journals CD4 Binding Affinity Determines Human Immunodeficiency Virus Type 1-Induced Alpha Interferon Production in Plasmacytoid Dendritic Cells

2008 ◽  
Vol 82 (17) ◽  
pp. 8900-8905 ◽  
Author(s):  
Sabrina Haupt ◽  
Norbert Donhauser ◽  
Chawaree Chaipan ◽  
Philipp Schuster ◽  
Bridget Puffer ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Dendritic Cells ◽  
Binding Affinity ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Plasmacytoid Dendritic Cells ◽  
Type I ◽  
Immunodeficiency Virus ◽  
Hiv 1

ABSTRACT Plasmacytoid dendritic cells (PDC) are major producers of type I interferons (IFN) in response to human immunodeficiency virus type 1 (HIV-1) infection. To better define the underlying mechanisms, we studied the magnitude of alpha IFN (IFN-α) induction by recombinant viruses containing changes in the Env protein that impair or disrupt CD4 binding or expressing primary env alleles with differential coreceptor tropism. We found that the CD4 binding affinity but not the viral coreceptor usage is critical for the attachment of autofluorescing HIV-1 to PDC and for subsequent IFN-α induction. Our results illustrate the importance of the gp120-CD4 interaction in determining HIV-1-induced immune stimulation via IFN-α production.

The TLR-mediated response of plasmacytoid dendritic cells is positively regulated by estradiol in vivo through cell-intrinsic estrogen receptor α signaling

Blood ◽  
2012 ◽  
Vol 119 (2) ◽  
pp. 454-464 ◽  
Author(s):  
Cyril Seillet ◽  
Sophie Laffont ◽  
Florence Trémollières ◽  
Nelly Rouquié ◽  
Claude Ribot ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Estrogen Receptor ◽  
Estrogen Receptor Α ◽  
Plasmacytoid Dendritic Cells ◽  
Type I Interferons ◽  
Type I ◽  
Genetic Ablation ◽  
17Β Estradiol ◽  
Female Host

Plasmacytoid dendritic cells (pDCs) produce large amounts of type I interferons (IFN-α/β) in response to viral or endogenous nucleic acids through activation of their endosomal Toll-like receptors (TLR-7 and TLR-9). Enhanced TLR-7–mediated IFN-α production by pDCs in women, compared with men, has been reported, but whether sex hormones, such as estrogens, are involved in this sex-based difference is unknown. Here we show, in humanized mice, that the TLR-7–mediated response of human pDCs is increased in female host mice relative to male. In a clinical trial, we establish that treatment of postmenopausal women with 17β-estradiol markedly enhances TLR-7– and TLR-9–dependent production of IFN-α by pDCs stimulated by synthetic ligands or by nucleic acid-containing immune complexes. In mice, we found exogenous and endogenous estrogens to promote the TLR-mediated cytokine secretion by pDCs through hematopoietic expression of estrogen receptor (ER) α. Genetic ablation of ERα gene in the DC lineage abrogated the enhancing effect of 17β-estradiol on their TLR-mediated production of IFN-α, showing that estrogens directly target pDCs in vivo. Our results uncover a previously unappreciated role for estrogens in regulating the innate functions of pDCs, which may account for sex-based differences in autoimmune and infectious diseases.

scholarly journals The Evolutionary Histories of Antiretroviral Proteins SERINC3 and SERINC5 Do Not Support an Evolutionary Arms Race in Primates

2016 ◽  
Vol 90 (18) ◽  
pp. 8085-8089 ◽  
Author(s):  
Ben Murrell ◽  
Thomas Vollbrecht ◽  
John Guatelli ◽  
Joel O. Wertheim
Keyword(s):  
Viral Infections ◽  
Arms Race ◽  
Restriction Factor ◽  
Restriction Factors ◽  
Arms Races ◽  
Host Restriction ◽  
Host Restriction Factor ◽  
Novel Host ◽  
Evolutionary Arms Race ◽  
Hiv 1

ABSTRACTMolecular evolutionary arms races between viruses and their hosts are important drivers of adaptation. These Red Queen dynamics have been frequently observed in primate retroviruses and their antagonists, host restriction factor genes, such as APOBEC3F/G, TRIM5-α, SAMHD1, and BST-2. Host restriction factors have experienced some of the most intense and pervasive adaptive evolution documented in primates. Recently, two novel host factors, SERINC3 and SERINC5, were identified as the targets of HIV-1 Nef, a protein crucial for the optimal infectivity of virus particles. Here, we compared the evolutionary fingerprints of SERINC3 and SERINC5 to those of other primate restriction factors and to a set of other genes with diverse functions. SERINC genes evolved in a manner distinct from the canonical arms race dynamics seen in the other restriction factors. Despite their antiviral activity against HIV-1 and other retroviruses, SERINC3 and SERINC5 have a relatively uneventful evolutionary history in primates.IMPORTANCERestriction factors are host proteins that block viral infection and replication. Many viruses, like HIV-1 and related retroviruses, evolved accessory proteins to counteract these restriction factors. The importance of these interactions is evidenced by the intense adaptive selection pressures that dominate the evolutionary histories of both the host and viral genes involved in this so-called arms race. The dynamics of these arms races can point to mechanisms by which these viral infections can be prevented. Two human genes, SERINC3 and SERINC5, were recently identified as targets of an HIV-1 accessory protein important for viral infectivity. Unexpectedly, we found that these SERINC genes, unlike other host restriction factor genes, show no evidence of a recent evolutionary arms race with viral pathogens.

scholarly journals Specific Deubiquitinating Enzymes Promote Host Restriction Factors Against HIV/SIV Viruses

2021 ◽  
Vol 12 ◽  
Author(s):  
Wenying Gao ◽  
Yajuan Rui ◽  
Guangquan Li ◽  
Chenyang Zhai ◽  
Jiaming Su ◽  
...  
Keyword(s):  
Viral Replication ◽  
Ectopic Expression ◽  
Specific Inhibitor ◽  
Restriction Factors ◽  
Deubiquitinating Enzymes ◽  
Host Restriction ◽  
Host Restriction Factors ◽  
Virion Infectivity Factor ◽  
Specific Protease ◽  
Hiv 1

Hijacking host ubiquitin pathways is essential for the replication of diverse viruses. However, the role of deubiquitinating enzymes (DUBs) in the interplay between viruses and the host is poorly characterized. Here, we demonstrate that specific DUBs are potent inhibitors of viral proteins from HIVs/simian immunodeficiency viruses (SIVs) that are involved in viral evasion of host restriction factors and viral replication. In particular, we discovered that T cell-functioning ubiquitin-specific protease 8 (USP8) is a potent and specific inhibitor of HIV-1 virion infectivity factor (Vif)-mediated apolipoprotein B mRNA-editing enzyme catalytic polypeptide-like 3 (APOBEC3)G (A3G) degradation. Ectopic expression of USP8 inhibited Vif-induced A3G degradation and suppressed wild-type HIV-1 infectivity even in the presence of Vif. In addition, specific DUBs repressed Vpr-, Vpu-, and Vpx-triggered host restriction factor degradation. Our study has revealed a previously unrecognized interplay between the host’s DUBs and viral replication. Enhancing the antiviral activity of DUBs therefore represents an attractive strategy against HIVs/SIVs.

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