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  1. Article ; Online: Early intervention with 3BNC117 and romidepsin at antiretroviral treatment initiation in people with HIV-1: a phase 1b/2a, randomized trial.

    Gunst, Jesper D / Pahus, Marie H / Rosás-Umbert, Miriam / Lu, I-Na / Benfield, Thomas / Nielsen, Henrik / Johansen, Isik S / Mohey, Rajesh / Østergaard, Lars / Klastrup, Vibeke / Khan, Maryam / Schleimann, Mariane H / Olesen, Rikke / Støvring, Henrik / Denton, Paul W / Kinloch, Natalie N / Copertino, Dennis C / Ward, Adam R / Alberto, Winiffer D Conce /
    Nielsen, Silke D / Puertas, Maria C / Ramos, Victor / Reeves, Jacqueline D / Petropoulos, Christos J / Martinez-Picado, Javier / Brumme, Zabrina L / Jones, R Brad / Fox, Julie / Tolstrup, Martin / Nussenzweig, Michel C / Caskey, Marina / Fidler, Sarah / Søgaard, Ole S

    Nature medicine

    2022  Volume 28, Issue 11, Page(s) 2424–2435

    Abstract: Attempts to reduce the human immunodeficiency virus type 1 (HIV-1) reservoir and induce antiretroviral therapy (ART)-free virologic control have largely been unsuccessful. In this phase 1b/2a, open-label, randomized controlled trial using a four-group ... ...

    Abstract Attempts to reduce the human immunodeficiency virus type 1 (HIV-1) reservoir and induce antiretroviral therapy (ART)-free virologic control have largely been unsuccessful. In this phase 1b/2a, open-label, randomized controlled trial using a four-group factorial design, we investigated whether early intervention in newly diagnosed people with HIV-1 with a monoclonal anti-HIV-1 antibody with a CD4-binding site, 3BNC117, followed by a histone deacetylase inhibitor, romidepsin, shortly after ART initiation altered the course of HIV-1 infection ( NCT03041012 ). The trial was undertaken in five hospitals in Denmark and two hospitals in the United Kingdom. The coprimary endpoints were analysis of initial virus decay kinetics and changes in the frequency of CD4
    MeSH term(s) Female ; Humans ; Male ; Anti-Retroviral Agents/therapeutic use ; Anti-Retroviral Agents/pharmacology ; CD4-Positive T-Lymphocytes ; Depsipeptides/therapeutic use ; Depsipeptides/pharmacology ; HIV Infections ; HIV-1 ; Proviruses ; Viral Load
    Chemical Substances Anti-Retroviral Agents ; Depsipeptides ; romidepsin (CX3T89XQBK)
    Language English
    Publishing date 2022-10-17
    Publishing country United States
    Document type Clinical Trial, Phase I ; Clinical Trial, Phase II ; Journal Article ; Randomized Controlled Trial ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 1220066-9
    ISSN 1546-170X ; 1078-8956
    ISSN (online) 1546-170X
    ISSN 1078-8956
    DOI 10.1038/s41591-022-02023-7
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Zs.A 4212: Show issues Location:
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  2. Article ; Online: TLR2 and TLR7 mediate distinct immunopathological and antiviral plasmacytoid dendritic cell responses to SARS-CoV-2 infection.

    van der Sluis, Renée M / Cham, Lamin B / Gris-Oliver, Albert / Gammelgaard, Kristine R / Pedersen, Jesper G / Idorn, Manja / Ahmadov, Ulvi / Hernandez, Sabina Sanches / Cémalovic, Ena / Godsk, Stine H / Thyrsted, Jacob / Gunst, Jesper D / Nielsen, Silke D / Jørgensen, Janni J / Bjerg, Tobias Wang / Laustsen, Anders / Reinert, Line S / Olagnier, David / Bak, Rasmus O /
    Kjolby, Mads / Holm, Christian K / Tolstrup, Martin / Paludan, Søren R / Kristensen, Lasse S / Søgaard, Ole S / Jakobsen, Martin R

    The EMBO journal

    2022  Volume 41, Issue 10, Page(s) e109622

    Abstract: Understanding the molecular pathways driving the acute antiviral and inflammatory response to SARS-CoV-2 infection is critical for developing treatments for severe COVID-19. Here, we find decreasing number of circulating plasmacytoid dendritic cells ( ... ...

    Abstract Understanding the molecular pathways driving the acute antiviral and inflammatory response to SARS-CoV-2 infection is critical for developing treatments for severe COVID-19. Here, we find decreasing number of circulating plasmacytoid dendritic cells (pDCs) in COVID-19 patients early after symptom onset, correlating with disease severity. pDC depletion is transient and coincides with decreased expression of antiviral type I IFNα and of systemic inflammatory cytokines CXCL10 and IL-6. Using an in vitro stem cell-based human pDC model, we further demonstrate that pDCs, while not supporting SARS-CoV-2 replication, directly sense the virus and in response produce multiple antiviral (interferons: IFNα and IFNλ1) and inflammatory (IL-6, IL-8, CXCL10) cytokines that protect epithelial cells from de novo SARS-CoV-2 infection. Via targeted deletion of virus-recognition innate immune pathways, we identify TLR7-MyD88 signaling as crucial for production of antiviral interferons (IFNs), whereas Toll-like receptor (TLR)2 is responsible for the inflammatory IL-6 response. We further show that SARS-CoV-2 engages the receptor neuropilin-1 on pDCs to selectively mitigate the antiviral interferon response, but not the IL-6 response, suggesting neuropilin-1 as potential therapeutic target for stimulation of TLR7-mediated antiviral protection.
    MeSH term(s) COVID-19/immunology ; COVID-19/pathology ; Cytokines/metabolism ; Dendritic Cells/immunology ; Dendritic Cells/pathology ; Humans ; Interferon Type I/immunology ; Interferon-alpha/immunology ; Interleukin-6/immunology ; Neuropilin-1/immunology ; SARS-CoV-2 ; Toll-Like Receptor 2/immunology ; Toll-Like Receptor 7/immunology
    Chemical Substances Cytokines ; Interferon Type I ; Interferon-alpha ; Interleukin-6 ; TLR2 protein, human ; TLR7 protein, human ; Toll-Like Receptor 2 ; Toll-Like Receptor 7 ; Neuropilin-1 (144713-63-3)
    Language English
    Publishing date 2022-03-01
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 586044-1
    ISSN 1460-2075 ; 0261-4189
    ISSN (online) 1460-2075
    ISSN 0261-4189
    DOI 10.15252/embj.2021109622
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    Zs.A 1808: Show issues Location:
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  3. Article ; Online: Distinct SARS-CoV-2 sensing pathways in pDCs driving TLR7-antiviral vs. TLR2-immunopathological responses in COVID-19

    van der Sluis, Renee M / Cham, Lamin B / Oliver, Alberg Gris / Gammelgaard, Kristine Raaby / Pedersen, Jesper Geert / Idorn, Manja / Ahmodov, Ulvi / Hernandez, Sabina S / Cemalovic, Ena / Godsk, Stine H / Thyrsted, Jakob / Gunst, Jesper D / Nielsen, Silke D / Jorgensen, Janni j / Bjerg, Tobias W / Laustsen, Anders / Reinert, Line / Olagnier, David / Bak, Rasmus O. /
    Kjolby, Mads / Holm, Christian Kanstrup / Tolstrup, Martin / Paludan, Soren R. / Kristensen, lasse S / Sogaard, Ole S / Jakobsen, Martin R

    bioRxiv

    Abstract: Understanding the molecular pathways driving the acute antiviral and inflammatory response to SARS-CoV-2 infection is critical for developing treatments for severe COVID-19. Here we show that in COVID-19 patients, circulating plasmacytoid dendritic cells ...

    Abstract Understanding the molecular pathways driving the acute antiviral and inflammatory response to SARS-CoV-2 infection is critical for developing treatments for severe COVID-19. Here we show that in COVID-19 patients, circulating plasmacytoid dendritic cells (pDCs) decline early after symptom onset and this correlated with COVID-19 disease severity. This transient depletion coincides with decreased expression of antiviral type I IFNα and the systemic inflammatory cytokines CXCL10 and IL-6. Importantly, COVID-19 disease severity correlated with decreased pDC frequency in peripheral blood. Using an in vitro stem cell-based human pDC model, we demonstrate that pDCs directly sense SARS-CoV-2 and in response produce multiple antiviral (IFNα and IFNλ1) and inflammatory (IL-6, IL-8, CXCL10) cytokines. This immune response is sufficient to protect epithelial cells from de novo SARS-CoV-2 infection. Targeted deletion of specific sensing pathways identified TLR7-MyD88 signaling as being crucial for production of the antiviral IFNs, whereas TLR2 is responsible for the inflammatory IL-6 response. Surprisingly, we found that SARS-CoV-2 engages the neuropilin-1 receptor on pDCs to mitigate the antiviral IFNs but not the IL-6 response. These results demonstrate distinct sensing pathways used by pDCs to elicit antiviral vs. immunopathological responses to SARS-CoV-2 and suggest that targeting neuropilin-1 on pDCs may be clinically relevant for mounting TLR7-mediated antiviral protection.
    Keywords covid19
    Language English
    Publishing date 2021-11-24
    Publisher Cold Spring Harbor Laboratory
    Document type Article ; Online
    DOI 10.1101/2021.11.23.469755
    Database COVID19

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