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4 results on '"Anouk Van Nuffel"'

1. HIV Triggers a cGAS-Dependent, Vpu- and Vpr-Regulated Type I Interferon Response in CD4+ T Cells

Author

Jolien Vermeire, Ferdinand Roesch, Daniel Sauter, Réjane Rua, Dominik Hotter, Anouk Van Nuffel, Hanne Vanderstraeten, Evelien Naessens, Veronica Iannucci, Alessia Landi, Wojciech Witkowski, Ann Baeyens, Frank Kirchhoff, and Bruno Verhasselt

Subjects
HIV, Vpr, Vpu, interferon, cGAS, T cells, dendritic cells, innate sensing, NF-κB, CD4, Biology (General), QH301-705.5
Abstract

Several pattern-recognition receptors sense HIV-1 replication products and induce type I interferon (IFN-I) production under specific experimental conditions. However, it is thought that viral sensing and IFN induction are virtually absent in the main target cells of HIV-1 in vivo. Here, we show that activated CD4+ T cells sense HIV-1 infection through the cytosolic DNA sensor cGAS and mount a bioactive IFN-I response. Efficient induction of IFN-I by HIV-1 infection requires proviral integration and is regulated by newly expressed viral accessory proteins: Vpr potentiates, while Vpu suppresses cGAS-dependent IFN-I induction. Furthermore, Vpr also amplifies innate sensing of HIV-1 infection in Vpx-treated dendritic cells. Our results identify cGAS as mediator of an IFN-I response to HIV-1 infection in CD4+ T cells and demonstrate that this response is modulated by the viral accessory proteins Vpr and Vpu. Thus, viral innate immune evasion is incomplete in the main target cells of HIV-1.

Published
2016
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2. Virion encapsidated HIV-1 Vpr induces NFAT to prime non-activated T cells for productive infection

Author

Kristin Höhne, Ramona Businger, Anouk van Nuffel, Sebastian Bolduan, Herwig Koppensteiner, Ann Baeyens, Jolien Vermeire, Eva Malatinkova, Bruno Verhasselt, and Michael Schindler

Subjects
hiv-1, vpr, nfat, productive t-cell infection, Biology (General), QH301-705.5
Abstract

The majority of T cells encountered by HIV-1 are non-activated and do not readily allow productive infection. HIV-1 Vpr is highly abundant in progeny virions, and induces signalling and HIV-1 LTR transcription. We hence hypothesized that Vpr might be a determinant of non-activated T-cell infection. Virion-delivered Vpr activated nuclear factor of activated T cells (NFAT) through Ca2+ influx and interference with the NFAT export kinase GSK3β. This leads to NFAT translocation and accumulation within the nucleus and was required for productive infection of unstimulated primary CD4+ T cells. A mutagenesis approach revealed correlation of Vpr-mediated NFAT activation with its ability to enhance LTR transcription and mediate cell cycle arrest. Upon NFAT inhibition, Vpr did not augment resting T-cell infection, and showed reduced G2/M arrest and LTR transactivation. Altogether, Vpr renders unstimulated T cells more permissive for productive HIV-1 infection and stimulates activation of productively infected as well as virus-exposed T cells. Therefore, it could be involved in the establishment and reactivation of HIV-1 from viral reservoirs and might have an impact on the levels of immune activation, which are determinants of HIV-1 pathogenesis.

Published
2016
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3. HIV Triggers a cGAS-Dependent, Vpu- and Vpr-Regulated Type I Interferon Response in CD4+ T Cells

Author

Daniel Sauter, Anouk Van Nuffel, Bruno Verhasselt, Ann Baeyens, Alessia Landi, Evelien Naessens, Ferdinand Roesch, Wojciech Witkowski, Dominik Hotter, Hanne Vanderstraeten, Veronica Iannucci, Frank Kirchhoff, Jolien Vermeire, and Réjane Rua

Subjects
0301 basic medicine, CD4-Positive T-Lymphocytes, viruses, NF-KAPPA-B, Human Immunodeficiency Virus Proteins, HIV Infections, NF-κB, chemistry.chemical_compound, Interferon, INFECTION, Medicine and Health Sciences, Viral Regulatory and Accessory Proteins, Viral Accessory Proteins, Receptor, lcsh:QH301-705.5, virus diseases, vpr Gene Products, Human Immunodeficiency Virus, interferon, IMMUNODEFICIENCY-VIRUS TYPE-1, Nucleotidyltransferases, INNATE IMMUNE-RESPONSE, 3. Good health, Interferon Type I, PROTEIN-R, medicine.drug, EXPRESSION, T cells, Biology, Vpr, DENDRITIC CELLS, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, Mediator, Vpu, medicine, innate sensing, Humans, dendritic cells, Innate immune system, T-cells, DISEASE PROGRESSION, HEK 293 cells, Lentivirus, HIV, SENSOR, Virology, Immunity, Innate, CD4, 030104 developmental biology, HEK293 Cells, chemistry, lcsh:Biology (General), REPLICATION, HIV-1, Interferon type I, cGAS
Abstract

SummarySeveral pattern-recognition receptors sense HIV-1 replication products and induce type I interferon (IFN-I) production under specific experimental conditions. However, it is thought that viral sensing and IFN induction are virtually absent in the main target cells of HIV-1 in vivo. Here, we show that activated CD4+ T cells sense HIV-1 infection through the cytosolic DNA sensor cGAS and mount a bioactive IFN-I response. Efficient induction of IFN-I by HIV-1 infection requires proviral integration and is regulated by newly expressed viral accessory proteins: Vpr potentiates, while Vpu suppresses cGAS-dependent IFN-I induction. Furthermore, Vpr also amplifies innate sensing of HIV-1 infection in Vpx-treated dendritic cells. Our results identify cGAS as mediator of an IFN-I response to HIV-1 infection in CD4+ T cells and demonstrate that this response is modulated by the viral accessory proteins Vpr and Vpu. Thus, viral innate immune evasion is incomplete in the main target cells of HIV-1.

Published
2016

4. HIV-1 Vpr N-terminal tagging affects alternative splicing of the viral genome

Author

Karin Weening, Linos Vandekerckhove, Evelien Naessens, Kris Gevaert, Sven Eyckerman, Eva Claeys, Wim Trypsteen, Bruno Verhasselt, Ann Baeyens, Anne-Marie Reilly, and Anouk Van Nuffel

Subjects
0301 basic medicine, RNA Folding, In silico, viruses, Genome, Viral, Biology, Genome, Article, Cell Line, Nucleic acid secondary structure, 03 medical and health sciences, REV FUNCTION, IMMUNODEFICIENCY-VIRUS, INFECTION, Humans, RNA, Messenger, Genetics, Messenger RNA, Multidisciplinary, 030102 biochemistry & molecular biology, PRE-MESSENGER-RNA, Alternative splicing, Intron, Biology and Life Sciences, SITE, vpr Gene Products, Human Immunodeficiency Virus, IN-VITRO, Alternative Splicing, 030104 developmental biology, Regulatory sequence, RNA splicing, REPLICATION, RNA SECONDARY STRUCTURE, HIV-1, RNA, Viral, U1 SNRNA, STRUCTURE PREDICTION
Abstract

To facilitate studies on Vpr function in replicating HIV-1, we aimed to tag the protein in an infectious virus. First we showed that N-, but not C-terminal HA/FLAG tagging of Vpr protein preserves Vpr cytopathicity. Cloning the tags into proviral DNA however ablated viral production and replication. By construction of additional viral variants we could show this defect was not protein- but RNA-dependent and sequence specific, and characterized by oversplicing of the genomic RNA. Simulation of genomic RNA folding suggested that introduction of the tag sequence induced an alternative folding structure in a region enriched in splice sites and splicing regulatory sequences. In silico predictions identified the HA/His6-Vpr tagging in HIV-1 to affect mRNA folding less than HA/FLAG-Vpr tagging. In vitro infectivity and mRNA splice pattern improved but did not reach wild-type values. Thus, sequence-specific insertions may interfere with mRNA splicing, possibly due to altered RNA folding. Our results point to the complexity of viral RNA genome sequence interactions. This should be taken into consideration when designing viral manipulation strategies, for both research as for biological interventions.

Published
2016

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