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  1. Article ; Online: Spotlight on HIV-1 Nef

    Oliver T. Fackler

    Viruses, Vol 7, Iss 12, Pp 6730-

    SERINC3 and SERINC5 Identified as Restriction Factors Antagonized by the Pathogenesis Factor

    2015  Volume 6738

    Abstract: The Nef protein is an accessory gene product encoded by human immunodeficiency virus types 1 and 2 (HIV-1/-2) and simian immunodeficiency virus (SIV) that boosts virus replication in the infected host and accelerates disease progression. Unlike the HIV-1 ...

    Abstract The Nef protein is an accessory gene product encoded by human immunodeficiency virus types 1 and 2 (HIV-1/-2) and simian immunodeficiency virus (SIV) that boosts virus replication in the infected host and accelerates disease progression. Unlike the HIV-1 accessory proteins Vif, Vpr and Vpu, Nef was, until recently, not known to antagonize the antiviral activity of a host cell restriction factor. Two recent reports now describe the host cell proteins serine incorporator 3 and 5 (SERINC3 and SERINC5) as potent inhibitors of HIV-1 particle infectivity and demonstrate that Nef counteracts these effects. These findings establish SERINC3/5 as restrictions to HIV replication in human cells and define a novel activity for the HIV pathogenesis factor Nef.
    Keywords HIV-1 ; restriction factors ; Nef protein ; virion infectivity ; SERINC3 ; SERINC5 ; Microbiology ; QR1-502 ; Science ; Q
    Language English
    Publishing date 2015-12-01T00:00:00Z
    Publisher MDPI AG
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  2. Article ; Online: Environmental Restrictions

    Samy Sid Ahmed / Nils Bundgaard / Frederik Graw / Oliver T. Fackler

    Cells, Vol 9, Iss 1112, p

    A New Concept Governing HIV-1 Spread Emerging from Integrated Experimental-Computational Analysis of Tissue-Like 3D Cultures

    2020  Volume 1112

    Abstract: HIV-1 can use cell-free and cell-associated transmission modes to infect new target cells, but how the virus spreads in the infected host remains to be determined. We recently established 3D collagen cultures to study HIV-1 spread in tissue-like ... ...

    Abstract HIV-1 can use cell-free and cell-associated transmission modes to infect new target cells, but how the virus spreads in the infected host remains to be determined. We recently established 3D collagen cultures to study HIV-1 spread in tissue-like environments and applied iterative cycles of experimentation and computation to develop a first in silico model to describe the dynamics of HIV-1 spread in complex tissue. These analyses (i) revealed that 3D collagen environments restrict cell-free HIV-1 infection but promote cell-associated virus transmission and (ii) defined that cell densities in tissue dictate the efficacy of these transmission modes for virus spread. In this review, we discuss, in the context of the current literature, the implications of this study for our understanding of HIV-1 spread in vivo, which aspects of in vivo physiology this integrated experimental–computational analysis takes into account, and how it can be further improved experimentally and in silico.
    Keywords HIV-1 spread ; cell-free infection ; cell–cell transmission ; 3D cultures ; mathematical modeling ; environmental restriction ; Biology (General) ; QH301-705.5
    Subject code 612
    Language English
    Publishing date 2020-04-01T00:00:00Z
    Publisher MDPI AG
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  3. Article ; Online: Contact-dependent inhibition of HIV-1 replication in ex vivo human tonsil cultures by polymorphonuclear neutrophils

    Tatjana Reif / Gerhard Dyckhoff / Ralph Hohenberger / Carl-Christian Kolbe / Henning Gruell / Florian Klein / Eicke Latz / Bettina Stolp / Oliver T. Fackler

    Cell Reports Medicine, Vol 2, Iss 6, Pp 100317- (2021)

    2021  

    Abstract: Summary: Polymorphonuclear neutrophils (PMNs), the most abundant white blood cells, are recruited rapidly to sites of infection to exert potent anti-microbial activity. Information regarding their role in infection with human immunodeficiency virus (HIV) ...

    Abstract Summary: Polymorphonuclear neutrophils (PMNs), the most abundant white blood cells, are recruited rapidly to sites of infection to exert potent anti-microbial activity. Information regarding their role in infection with human immunodeficiency virus (HIV) is limited. Here we report that addition of PMNs to HIV-infected cultures of human tonsil tissue or peripheral blood mononuclear cells causes immediate and long-lasting suppression of HIV-1 spread and virus-induced depletion of CD4 T cells. This inhibition of HIV-1 spread strictly requires PMN contact with infected cells and is not mediated by soluble factors. 2-Photon (2PM) imaging visualized contacts of PMNs with HIV-1-infected CD4 T cells in tonsil tissue that do not result in lysis or uptake of infected cells. The anti-HIV activity of PMNs also does not involve degranulation, formation of neutrophil extracellular traps, or integrin-dependent cell communication. These results reveal that PMNs efficiently blunt HIV-1 replication in primary target cells and tissue by an unconventional mechanism.
    Keywords HIV-1 replication ; polymorphonuclear neutrophils ; antiviral activity ; human tonsil explant culture ; Medicine (General) ; R5-920
    Language English
    Publishing date 2021-06-01T00:00:00Z
    Publisher Elsevier
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  4. Article ; Online: FAMoS

    Michael Gabel / Tobias Hohl / Andrea Imle / Oliver T Fackler / Frederik Graw

    PLoS Computational Biology, Vol 15, Iss 8, p e

    A Flexible and dynamic Algorithm for Model Selection to analyse complex systems dynamics.

    2019  Volume 1007230

    Abstract: Most biological systems are difficult to analyse due to a multitude of interacting components and the concomitant lack of information about the essential dynamics. Finding appropriate models that provide a systematic description of such biological ... ...

    Abstract Most biological systems are difficult to analyse due to a multitude of interacting components and the concomitant lack of information about the essential dynamics. Finding appropriate models that provide a systematic description of such biological systems and that help to identify their relevant factors and processes can be challenging given the sheer number of possibilities. Model selection algorithms that evaluate the performance of a multitude of different models against experimental data provide a useful tool to identify appropriate model structures. However, many algorithms addressing the analysis of complex dynamical systems, as they are often used in biology, compare a preselected number of models or rely on exhaustive searches of the total model space which might be unfeasible dependent on the number of possibilities. Therefore, we developed an algorithm that is able to perform model selection on complex systems and searches large model spaces in a dynamical way. Our algorithm includes local and newly developed non-local search methods that can prevent the algorithm from ending up in local minima of the model space by accounting for structurally similar processes. We tested and validated the algorithm based on simulated data and showed its flexibility for handling different model structures. We also used the algorithm to analyse experimental data on the cell proliferation dynamics of CD4+ and CD8+ T cells that were cultured under different conditions. Our analyses indicated dynamical changes within the proliferation potential of cells that was reduced within tissue-like 3D ex vivo cultures compared to suspension. Due to the flexibility in handling various model structures, the algorithm is applicable to a large variety of different biological problems and represents a useful tool for the data-oriented evaluation of complex model spaces.
    Keywords Biology (General) ; QH301-705.5
    Subject code 006
    Language English
    Publishing date 2019-08-01T00:00:00Z
    Publisher Public Library of Science (PLoS)
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  5. Article ; Online: Genomic profiling of HIV-1 integration in microglia cells links viral integration to the topologically associated domains

    Mona Rheinberger / Ana Luisa Costa / Martin Kampmann / Dunja Glavas / Iart Luca Shytaj / Sheetal Sreeram / Carlotta Penzo / Nadine Tibroni / Yoelvis Garcia-Mesa / Konstantin Leskov / Oliver T. Fackler / Kristian Vlahovicek / Jonathan Karn / Bojana Lucic / Carl Herrmann / Marina Lusic

    Cell Reports, Vol 42, Iss 2, Pp 112110- (2023)

    2023  

    Abstract: Summary: HIV-1 encounters the hierarchically organized host chromatin to stably integrate and persist in anatomically distinct latent reservoirs. The contribution of genome organization in HIV-1 infection has been largely understudied across different ... ...

    Abstract Summary: HIV-1 encounters the hierarchically organized host chromatin to stably integrate and persist in anatomically distinct latent reservoirs. The contribution of genome organization in HIV-1 infection has been largely understudied across different HIV-1 targets. Here, we determine HIV-1 integration sites (ISs), associate them with chromatin and expression signatures at different genomic scales in a microglia cell model, and profile them together with the primary T cell reservoir. HIV-1 insertions into introns of actively transcribed genes with IS hotspots in genic and super-enhancers, characteristic of blood cells, are maintained in the microglia cell model. Genome organization analysis reveals dynamic CCCTC-binding factor (CTCF) clusters in cells with active and repressed HIV-1 transcription, whereas CTCF removal impairs viral integration. We identify CTCF-enriched topologically associated domain (TAD) boundaries with signatures of transcriptionally active chromatin as HIV-1 integration determinants in microglia and CD4+ T cells, highlighting the importance of host genome organization in HIV-1 infection.
    Keywords CP: Molecular biology ; Biology (General) ; QH301-705.5
    Language English
    Publishing date 2023-02-01T00:00:00Z
    Publisher Elsevier
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  6. Article ; Online: How HIV Takes Advantage of the Cytoskeleton in Entry and Replication

    Oliver T. Fackler / Bettina Stolp

    Viruses, Vol 3, Iss 4, Pp 293-

    2011  Volume 311

    Abstract: The host cell cytoskeleton plays a key role in the life cycle of viral pathogens whose propagation depends on mandatory intracellular steps. Accordingly, also the human immunodeficiency virus type 1 (HIV-1) has evolved strategies to exploit and modulate ... ...

    Abstract The host cell cytoskeleton plays a key role in the life cycle of viral pathogens whose propagation depends on mandatory intracellular steps. Accordingly, also the human immunodeficiency virus type 1 (HIV-1) has evolved strategies to exploit and modulate in particular the actin cytoskeleton for its purposes. This review will recapitulate recent findings on how HIV-1 hijacks the cytoskeleton to facilitate entry into, transport within and egress from host cells as well as to commandeer communication of infected with uninfected bystander cells.
    Keywords HIV ; actin cytoskeleton ; entry ; Nef ; cofilin ; Microbiology ; QR1-502 ; Science ; Q ; DOAJ:Microbiology ; DOAJ:Biology ; DOAJ:Biology and Life Sciences
    Language English
    Publishing date 2011-03-01T00:00:00Z
    Publisher MDPI AG
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  7. Article ; Online: SERINC5 Is an Unconventional HIV Restriction Factor That Is Upregulated during Myeloid Cell Differentiation

    Ariane Zutz / Christian Schölz / Stephanie Schneider / Virginia Pierini / Maximilian Münchhoff / Kathrin Sutter / Georg Wittmann / Ulf Dittmer / Rika Draenert / Johannes R. Bogner / Oliver T. Fackler / Oliver T. Keppler

    Journal of Innate Immunity, Pp 1-

    2020  Volume 11

    Abstract: Classical antiviral restriction factors promote cellular immunity by their ability to interfere with virus replication and induction of their expression by proinflammatory cytokines such as interferons. The serine incorporator proteins SERINC3 and ... ...

    Abstract Classical antiviral restriction factors promote cellular immunity by their ability to interfere with virus replication and induction of their expression by proinflammatory cytokines such as interferons. The serine incorporator proteins SERINC3 and SERINC5 potently reduce the infectivity of HIV-1 particles when overexpressed, and RNA interference or knockout approaches in T cells have indicated antiviral activity also of the endogenous proteins. Due to lack of reagents for detection of endogenous SERINC proteins, it is still unclear whether SERINC3/5 are expressed to functionally relevant levels in different primary target cells of HIV infection and how the expression levels of these innate immunity factors are regulated. In the current study, analysis of SERINC3/5 mRNA steady-state levels in primary lymphoid and monocyte-derived cells revealed selective induction of their expression upon differentiation of myeloid cells. Contrary to classical antiviral restriction factors, various antiviral α-interferon subtypes and proinflammatory interleukins had no effect on SERINC levels, which were also not dysregulated in CD4+ T cells and monocytes isolated from patients with chronic HIV-1 infection. Notably, HIV-1 particles produced by terminally differentiated monocyte-derived macrophages with high SERINC5 expression, but not by low-expressing monocytes, showed a Nef-dependent infectivity defect. Overall, these findings suggest endogenous expression of SERINC5 to antivirally active levels in macrophages. Our results classify SERINC5 as an unconventional HIV-1 restriction factor whose expression is specifically induced upon differentiation of cells towards the myeloid lineage.
    Keywords serinc5 ; innate restriction factor ; adaptive immunity ; hiv ; myeloid cell differentiation ; Medicine ; R ; Internal medicine ; RC31-1245
    Subject code 570
    Language English
    Publishing date 2020-01-01T00:00:00Z
    Publisher Karger Publishers
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  8. Article ; Online: GPCR-induced calcium transients trigger nuclear actin assembly for chromatin dynamics

    Ying Wang / Alice Sherrard / Bing Zhao / Michael Melak / Jonathan Trautwein / Eva-Maria Kleinschnitz / Nikolaos Tsopoulidis / Oliver T. Fackler / Carsten Schwan / Robert Grosse

    Nature Communications, Vol 10, Iss 1, Pp 1-

    2019  Volume 9

    Abstract: The extracellular cues regulating filamentous actin formation in somatic cell nuclei are unclear. Here, the authors show that activated GPCR signalling initiates transient accumulation of nuclear F-actin/formation in nuclear actin filaments, driven by ... ...

    Abstract The extracellular cues regulating filamentous actin formation in somatic cell nuclei are unclear. Here, the authors show that activated GPCR signalling initiates transient accumulation of nuclear F-actin/formation in nuclear actin filaments, driven by calcium and requiring the nucleator Formin INF2.
    Keywords Science ; Q
    Language English
    Publishing date 2019-11-01T00:00:00Z
    Publisher Nature Publishing Group
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  9. Article ; Online: GPCR-induced calcium transients trigger nuclear actin assembly for chromatin dynamics

    Ying Wang / Alice Sherrard / Bing Zhao / Michael Melak / Jonathan Trautwein / Eva-Maria Kleinschnitz / Nikolaos Tsopoulidis / Oliver T. Fackler / Carsten Schwan / Robert Grosse

    Nature Communications, Vol 10, Iss 1, Pp 1-

    2019  Volume 9

    Abstract: The extracellular cues regulating filamentous actin formation in somatic cell nuclei are unclear. Here, the authors show that activated GPCR signalling initiates transient accumulation of nuclear F-actin/formation in nuclear actin filaments, driven by ... ...

    Abstract The extracellular cues regulating filamentous actin formation in somatic cell nuclei are unclear. Here, the authors show that activated GPCR signalling initiates transient accumulation of nuclear F-actin/formation in nuclear actin filaments, driven by calcium and requiring the nucleator Formin INF2.
    Keywords Science ; Q
    Language English
    Publishing date 2019-11-01T00:00:00Z
    Publisher Nature Portfolio
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  10. Article ; Online: HIV-1 Nef employs two distinct mechanisms to modulate Lck subcellular localization and TCR induced actin remodeling.

    Claudia Haller / Susanne Rauch / Oliver T Fackler

    PLoS ONE, Vol 2, Iss 11, p e

    2007  Volume 1212

    Abstract: The Nef protein acts as critical factor during HIV pathogenesis by increasing HIV replication in vivo via the modulation of host cell vesicle transport and signal transduction processes. Recent studies suggested that Nef alters formation and function of ... ...

    Abstract The Nef protein acts as critical factor during HIV pathogenesis by increasing HIV replication in vivo via the modulation of host cell vesicle transport and signal transduction processes. Recent studies suggested that Nef alters formation and function of immunological synapses (IS), thereby modulating exogenous T-cell receptor (TCR) stimulation to balance between partial T cell activation required for HIV-1 spread and prevention of activation induced cell death. Alterations of IS function by Nef include interference with cell spreading and actin polymerization upon TCR engagement, a pronounced intracellular accumulation of the Src kinase Lck and its reduced IS recruitment. Here we use a combination of Nef mutagenesis and pharmacological inhibition to analyze the relative contribution of these effects to Nef mediated alterations of IS organization and function on TCR stimulatory surfaces. Inhibition of actin polymerization and IS recruitment of Lck were governed by identical Nef determinants and correlated well with Nef's association with Pak2 kinase activity. In contrast, Nef mediated Lck endosomal accumulation was separable from these effects, occurred independently of Pak2, required integrity of the microtubule rather than the actin filament system and thus represents a distinct Nef activity. Finally, reduction of TCR signal transmission by Nef was linked to altered actin remodeling and Lck IS recruitment but did not require endosomal Lck rerouting. Thus, Nef affects IS function via multiple independent mechanisms to optimize virus replication in the infected host.
    Keywords Medicine ; R ; Science ; Q
    Subject code 570
    Language English
    Publishing date 2007-11-01T00:00:00Z
    Publisher Public Library of Science (PLoS)
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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