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  1. Article ; Online: Eliciting CD4-mimicking broadly neutralizing antibodies: new avenues towards the rational design of an HIV vaccine.

    Muecksch, Frauke / Fackler, Oliver T

    Signal transduction and targeted therapy

    2024  Volume 9, Issue 1, Page(s) 49

    MeSH term(s) Humans ; Broadly Neutralizing Antibodies ; AIDS Vaccines ; HIV Infections/prevention & control ; Antibodies, Neutralizing
    Chemical Substances Broadly Neutralizing Antibodies ; AIDS Vaccines ; Antibodies, Neutralizing
    Language English
    Publishing date 2024-02-29
    Publishing country England
    Document type Journal Article
    ZDB-ID 2886872-9
    ISSN 2059-3635 ; 2095-9907
    ISSN (online) 2059-3635
    ISSN 2095-9907
    DOI 10.1038/s41392-024-01776-6
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: Beyond Impairment of Virion Infectivity: New Activities of the Anti-HIV Host Cell Factor SERINC5.

    Sid Ahmed, Samy / Bajak, Kathrin / Fackler, Oliver T

    Viruses

    2024  Volume 16, Issue 2

    Abstract: Members of the serine incorporator (SERINC) protein family exert broad antiviral activity, and many viruses encode SERINC antagonists to circumvent these restrictions. Significant new insight was recently gained into the mechanisms that mediate ... ...

    Abstract Members of the serine incorporator (SERINC) protein family exert broad antiviral activity, and many viruses encode SERINC antagonists to circumvent these restrictions. Significant new insight was recently gained into the mechanisms that mediate restriction and antagonism. In this review, we summarize our current understanding of the mode of action and relevance of SERINC proteins in HIV-1 infection. Particular focus will be placed on recent findings that provided important new mechanistic insights into the restriction of HIV-1 virion infectivity, including the discovery of SERINC's lipid scramblase activity and its antagonism by the HIV-1 pathogenesis factor Nef. We also discuss the identification and implications of several additional antiviral activities by which SERINC proteins enhance pro-inflammatory signaling and reduce viral gene expression in myeloid cells. SERINC proteins emerge as versatile and multifunctional regulators of cell-intrinsic immunity against HIV-1 infection.
    MeSH term(s) Humans ; Membrane Proteins/metabolism ; nef Gene Products, Human Immunodeficiency Virus/metabolism ; Host-Pathogen Interactions ; HIV Infections ; Virion/metabolism ; Antiviral Agents
    Chemical Substances Membrane Proteins ; nef Gene Products, Human Immunodeficiency Virus ; Antiviral Agents ; SERINC5 protein, human
    Language English
    Publishing date 2024-02-12
    Publishing country Switzerland
    Document type Journal Article ; Review
    ZDB-ID 2516098-9
    ISSN 1999-4915 ; 1999-4915
    ISSN (online) 1999-4915
    ISSN 1999-4915
    DOI 10.3390/v16020284
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: Activation-neutral gene editing of tonsillar CD4 T cells for functional studies in human ex vivo tonsil cultures.

    Morath, Katharina / Sadhu, Lopamudra / Dyckhoff, Gerhard / Gapp, Madeleine / Keppler, Oliver T / Fackler, Oliver T

    Cell reports methods

    2024  Volume 4, Issue 1, Page(s) 100685

    Abstract: The molecular and immunological properties of tissue-resident resting CD4 T cells are understudied ... editing methodology ediTONSIL for CD4 T cells from human tonsils. Optimized CRISPR-Cas9 RNP nucleofection ... performed on multiple cell types in bulk cultures or on isolated CD4 T cells that can be labeled and ...

    Abstract The molecular and immunological properties of tissue-resident resting CD4 T cells are understudied due to the lack of suitable gene editing methods. Here, we describe the ex vivo culture and gene editing methodology ediTONSIL for CD4 T cells from human tonsils. Optimized CRISPR-Cas9 RNP nucleofection results in knockout efficacies of over 90% without requiring exogenous activation. Editing can be performed on multiple cell types in bulk cultures or on isolated CD4 T cells that can be labeled and reintroduced into their tissue environment. Importantly, CD4 T cells maintain their tissue-specific properties such as viability, activation state, or immunocompetence following reassembly into lymphoid aggregates. This highly efficient and versatile gene editing workflow for tonsillar CD4 T cells enables the dissection of molecular mechanisms in ex vivo cultures of human lymphoid tissue and can be adapted to other tonsil-resident cell types.
    MeSH term(s) Humans ; CD4-Positive T-Lymphocytes ; Palatine Tonsil ; Gene Editing ; Lymphoid Tissue
    Language English
    Publishing date 2024-01-10
    Publishing country United States
    Document type Journal Article
    ISSN 2667-2375
    ISSN (online) 2667-2375
    DOI 10.1016/j.crmeth.2023.100685
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article ; Online: Direct and indirect effects of CYTOR lncRNA regulate HIV gene expression.

    Kuzmina, Alona / Sadhu, Lopamudra / Hasanuzzaman, Md / Fujinaga, Koh / Schwartz, Jacob C / Fackler, Oliver T / Taube, Ran

    PLoS pathogens

    2024  Volume 20, Issue 4, Page(s) e1012172

    Abstract: ... functions of non-coding RNAs (ncRNA) in the context of T cell activation, HIV gene expression and ... following T cell stimulation. Functional studies show that CYTOR suppresses viral latency by directly ... cytoplasmic actin polymerization in response to T cell activation. In addition, treating HIV-infected cells ...

    Abstract The implementation of antiretroviral therapy (ART) has effectively restricted the transmission of Human Immunodeficiency Virus (HIV) and improved overall clinical outcomes. However, a complete cure for HIV remains out of reach, as the virus persists in a stable pool of infected cell reservoir that is resistant to therapy and thus a main barrier towards complete elimination of viral infection. While the mechanisms by which host proteins govern viral gene expression and latency are well-studied, the emerging regulatory functions of non-coding RNAs (ncRNA) in the context of T cell activation, HIV gene expression and viral latency have not yet been thoroughly explored. Here, we report the identification of the Cytoskeleton Regulator (CYTOR) long non-coding RNA (lncRNA) as an activator of HIV gene expression that is upregulated following T cell stimulation. Functional studies show that CYTOR suppresses viral latency by directly binding to the HIV promoter and associating with the cellular positive transcription elongation factor (P-TEFb) to activate viral gene expression. CYTOR also plays a global role in regulating cellular gene expression, including those involved in controlling actin dynamics. Depletion of CYTOR expression reduces cytoplasmic actin polymerization in response to T cell activation. In addition, treating HIV-infected cells with pharmacological inhibitors of actin polymerization reduces HIV gene expression. We conclude that both direct and indirect effects of CYTOR regulate HIV gene expression.
    Language English
    Publishing date 2024-04-25
    Publishing country United States
    Document type Journal Article
    ZDB-ID 2205412-1
    ISSN 1553-7374 ; 1553-7374
    ISSN (online) 1553-7374
    ISSN 1553-7374
    DOI 10.1371/journal.ppat.1012172
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  5. Article ; Online: ARPC5 isoforms and their regulation by calcium-calmodulin-N-WASP drive distinct Arp2/3-dependent actin remodeling events in CD4 T cells.

    Sadhu, Lopamudra / Tsopoulidis, Nikolaos / Hasanuzzaman, Md / Laketa, Vibor / Way, Michael / Fackler, Oliver T

    eLife

    2023  Volume 12

    Abstract: CD4 T cell activation induces nuclear and cytoplasmic actin polymerization via the Arp2/3 complex ... to activate cytokine expression and strengthen T cell receptor (TCR) signaling. Actin polymerization dynamics ... ARPC5L play a central role in coordinating distinct actin polymerization events in CD4 T ...

    Abstract CD4 T cell activation induces nuclear and cytoplasmic actin polymerization via the Arp2/3 complex to activate cytokine expression and strengthen T cell receptor (TCR) signaling. Actin polymerization dynamics and filament morphology differ between nucleus and cytoplasm. However, it is unclear how the Arp2/3 complex mediates distinct nuclear and cytoplasmic actin polymerization in response to a common stimulus. In humans, the ARP3, ARPC1, and ARPC5 subunits of the Arp2/3 complex exist as two different isoforms, resulting in complexes with different properties. Here, we show that the Arp2/3 subunit isoforms ARPC5 and ARPC5L play a central role in coordinating distinct actin polymerization events in CD4 T cells. While ARPC5L is heterogeneously expressed in individual CD4 T cells, it specifically drives nuclear actin polymerization upon T cell activation. In contrast, ARPC5 is evenly expressed in CD4 T cell populations and is required for cytoplasmic actin dynamics. Interestingly, nuclear actin polymerization triggered by a different stimulus, DNA replication stress, specifically requires ARPC5 but not ARPC5L. TCR signaling but not DNA replication stress induces nuclear actin polymerization via nuclear calcium-calmodulin signaling and N-WASP. Diversity in the molecular properties and individual expression patterns of ARPC5 subunit isoforms thus tailors Arp2/3-mediated actin polymerization to different physiological stimuli.
    MeSH term(s) Humans ; Actin-Related Protein 2/metabolism ; Actin-Related Protein 2-3 Complex/genetics ; Actin-Related Protein 2-3 Complex/metabolism ; Actins/metabolism ; Calcium/metabolism ; Calmodulin/metabolism ; CD4-Positive T-Lymphocytes/metabolism ; Protein Isoforms/genetics ; Protein Isoforms/metabolism ; Receptors, Antigen, T-Cell/metabolism
    Chemical Substances Actin-Related Protein 2 ; Actin-Related Protein 2-3 Complex ; Actins ; Calcium (SY7Q814VUP) ; Calmodulin ; Protein Isoforms ; Receptors, Antigen, T-Cell ; ARPC5 protein, human ; ACTR2 protein, human ; ACTR3 protein, human
    Language English
    Publishing date 2023-05-10
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2687154-3
    ISSN 2050-084X ; 2050-084X
    ISSN (online) 2050-084X
    ISSN 2050-084X
    DOI 10.7554/eLife.82450
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  6. Article ; Online: Spatial resolution of HIV-1 post-entry steps in resting CD4 T cells.

    Ananth, Swetha / Ambiel, Ina / Schifferdecker, Sandra / Müller, Thorsten G / Wratil, Paul R / Mejias-Perez, Ernesto / Kräusslich, Hans-Georg / Müller, Barbara / Keppler, Oliver T / Fackler, Oliver T

    Cell reports

    2024  Volume 43, Issue 3, Page(s) 113941

    Abstract: Resting CD4 T cells resist productive HIV-1 infection. The HIV-2/simian immunodeficiency virus ... CPSF6, and translocate to nuclear speckles in resting CD4 T cells. Reverse transcription ... pose important blocks to HIV-1 in resting CD4 T cells, and the limitation to reverse transcription ...

    Abstract Resting CD4 T cells resist productive HIV-1 infection. The HIV-2/simian immunodeficiency virus protein viral accessory protein X (Vpx) renders these cells permissive to infection, presumably by alleviating blocks at cytoplasmic reverse transcription and subsequent nuclear import of reverse-transcription/pre-integration complexes (RTC/PICs). Here, spatial analyses using quantitative virus imaging techniques reveal that HIV-1 capsids containing RTC/PICs are readily imported into the nucleus, recruit the host dependency factor CPSF6, and translocate to nuclear speckles in resting CD4 T cells. Reverse transcription, however, remains incomplete, impeding proviral integration and viral gene expression. Vpx or pharmacological inhibition of the deoxynucleotide triphosphohydrolase (dNTPase) activity of the restriction factor SAM domain and HD domain-containing protein 1 (SAMHD1) increases levels of nuclear reverse-transcribed cDNA and facilitates HIV-1 integration. Nuclear import and intranuclear transport of viral complexes therefore do not pose important blocks to HIV-1 in resting CD4 T cells, and the limitation to reverse transcription by SAMHD1's dNTPase activity constitutes the main pre-integration block to infection.
    MeSH term(s) Animals ; Humans ; HIV-1/genetics ; CD4-Positive T-Lymphocytes/metabolism ; SAM Domain and HD Domain-Containing Protein 1/metabolism ; HIV Infections ; HIV-2/genetics ; HIV Seropositivity ; Viral Regulatory and Accessory Proteins/metabolism ; Monomeric GTP-Binding Proteins/metabolism ; HEK293 Cells
    Chemical Substances SAM Domain and HD Domain-Containing Protein 1 (EC 3.1.5.-) ; Viral Regulatory and Accessory Proteins ; Monomeric GTP-Binding Proteins (EC 3.6.5.2)
    Language English
    Publishing date 2024-03-12
    Publishing country United States
    Document type Journal Article
    ZDB-ID 2649101-1
    ISSN 2211-1247 ; 2211-1247
    ISSN (online) 2211-1247
    ISSN 2211-1247
    DOI 10.1016/j.celrep.2024.113941
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  7. Article ; Online: Spotlight on HIV-1 Nef: SERINC3 and SERINC5 Identified as Restriction Factors Antagonized by the Pathogenesis Factor.

    Fackler, Oliver T

    Viruses

    2015  Volume 7, Issue 12, Page(s) 6730–6738

    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.
    MeSH term(s) HIV-1/immunology ; HIV-1/physiology ; Host-Pathogen Interactions ; Humans ; Membrane Proteins/antagonists & inhibitors ; Neoplasm Proteins/antagonists & inhibitors ; Receptors, Cell Surface/antagonists & inhibitors ; Virus Replication/drug effects ; nef Gene Products, Human Immunodeficiency Virus/metabolism
    Chemical Substances Membrane Proteins ; Neoplasm Proteins ; Receptors, Cell Surface ; SERINC3 protein, human ; SERINC5 protein, human ; nef Gene Products, Human Immunodeficiency Virus ; nef protein, Human immunodeficiency virus 1
    Language English
    Publishing date 2015-12-19
    Publishing country Switzerland
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2516098-9
    ISSN 1999-4915 ; 1999-4915
    ISSN (online) 1999-4915
    ISSN 1999-4915
    DOI 10.3390/v7122970
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  8. Article ; Online: Integrative analysis of pathogen replication and spread: zooming into increasing complexity.

    Fackler, Oliver T / Kräusslich, Hans-Georg

    FEBS letters

    2016  Volume 590, Issue 13, Page(s) 1855–1857

    Language English
    Publishing date 2016
    Publishing country England
    Document type Editorial
    ZDB-ID 212746-5
    ISSN 1873-3468 ; 0014-5793
    ISSN (online) 1873-3468
    ISSN 0014-5793
    DOI 10.1002/1873-3468.12253
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  9. Book ; Online ; Thesis: Characterization of the HIV-1 integration site landscape and chromatin determinants of integration in microglia cellular models and CD4+ T cells

    Rheinberger, Mona [Verfasser] / Fackler, Oliver Till [Akademischer Betreuer]

    2024  

    Author's details Mona Rheinberger ; Betreuer: Oliver T. Fackler
    Keywords Medizin, Gesundheit ; Medicine, Health
    Subject code sg610
    Language English
    Publisher Universitätsbibliothek Heidelberg
    Publishing place Heidelberg
    Document type Book ; Online ; Thesis
    Database Digital theses on the web

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  10. Article ; Online: SERINC5 Can Enhance Proinflammatory Cytokine Production by Primary Human Myeloid Cells in Response to Challenge with HIV-1 Particles.

    Pierini, Virginia / Gallucci, Lara / Stürzel, Christina M / Kirchhoff, Frank / Fackler, Oliver T

    Journal of virology

    2021  Volume 95, Issue 9

    Abstract: HIV-1 has to overcome physical barriers posed by host cell restriction factors (RFs) for efficient replication. Some RFs, including Trim5α and tetherin, trigger antiviral signaling in addition to directly impairing HIV replication. SERINC5 (S5) is an RF ... ...

    Abstract HIV-1 has to overcome physical barriers posed by host cell restriction factors (RFs) for efficient replication. Some RFs, including Trim5α and tetherin, trigger antiviral signaling in addition to directly impairing HIV replication. SERINC5 (S5) is an RF that is incorporated into HIV-1 particles to potently impair their infectivity and is efficiently antagonized by the viral pathogenesis factor Nef. Since effects of S5 on HIV-1 infectivity were mostly studied in reporter cell lines, we analyzed the effects of S5 during infection of primary HIV-1 target cells. In activated CD4
    MeSH term(s) CD4-Positive T-Lymphocytes/immunology ; Cytokines/metabolism ; Dendritic Cells/immunology ; HEK293 Cells ; HIV Infections/virology ; HIV-1/physiology ; Host Microbial Interactions ; Humans ; Leukocytes, Mononuclear/immunology ; Macrophages/immunology ; Membrane Proteins/metabolism ; Myeloid Cells/immunology ; Virion/metabolism ; nef Gene Products, Human Immunodeficiency Virus/metabolism
    Chemical Substances Cytokines ; Membrane Proteins ; SERINC5 protein, human ; nef Gene Products, Human Immunodeficiency Virus
    Language English
    Publishing date 2021-04-12
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 80174-4
    ISSN 1098-5514 ; 0022-538X
    ISSN (online) 1098-5514
    ISSN 0022-538X
    DOI 10.1128/JVI.02372-20
    Database MEDical Literature Analysis and Retrieval System OnLINE

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