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Article ; Online: Myeloid Dendritic Cells Induce HIV Latency in Proliferating CD4

Kumar, Nitasha A / van der Sluis, Renee M / Mota, Talia / Pascoe, Rachel / Evans, Vanessa A / Lewin, Sharon R / Cameron, Paul U

Journal of immunology (Baltimore, Md. : 1950)

2018 Volume 201, Issue 5, Page(s) 1468–1477

Abstract: HIV latency occurs predominantly in long-lived resting ... ...

Abstract	HIV latency occurs predominantly in long-lived resting CD4
MeSH term(s)	CD4-Positive T-Lymphocytes/immunology ; CD4-Positive T-Lymphocytes/pathology ; CD4-Positive T-Lymphocytes/virology ; Cell Proliferation ; Dendritic Cells/immunology ; Dendritic Cells/pathology ; Dendritic Cells/virology ; Enterotoxins/pharmacology ; HIV Infections/genetics ; HIV Infections/immunology ; HIV Infections/pathology ; HIV-1/physiology ; Humans ; Monocytes/immunology ; Monocytes/pathology ; Monocytes/virology ; Virus Latency/drug effects ; Virus Latency/genetics ; Virus Latency/immunology ; Virus Replication/drug effects ; Virus Replication/genetics ; Virus Replication/immunology
Chemical Substances	Enterotoxins ; enterotoxin B, staphylococcal (39424-53-8)
Language	English
Publishing date	2018-07-20
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	3056-9
ISSN	1550-6606 ; 0022-1767 ; 1048-3233 ; 1047-7381
ISSN (online)	1550-6606
ISSN	0022-1767 ; 1048-3233 ; 1047-7381
DOI	10.4049/jimmunol.1701233
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Article ; Online: Memory CD4

Rasmussen, Thomas A / Zerbato, Jennifer M / Rhodes, Ajantha / Tumpach, Carolin / Dantanarayana, Ashanti / McMahon, James H / Lau, Jillian S Y / Chang, J Judy / Gubser, Celine / Brown, Wendy / Hoh, Rebecca / Krone, Melissa / Pascoe, Rachel / Chiu, Chris Y / Bramhall, Michael / Lee, Hyun Jae / Haque, Ashraful / Fromentin, Rèmi / Chomont, Nicolas /

Milush, Jeffrey / Van der Sluis, Renee M / Palmer, Sarah / Deeks, Steven G / Cameron, Paul U / Evans, Vanessa / Lewin, Sharon R

Cell reports. Medicine

2022 Volume 3, Issue 10, Page(s) 100766

Abstract: Programmed cell death 1 (PD1) and cytotoxic T lymphocyte-associated protein 4 (CTLA4) suppress ... ...

Abstract	Programmed cell death 1 (PD1) and cytotoxic T lymphocyte-associated protein 4 (CTLA4) suppress CD4
MeSH term(s)	Humans ; CD4-Positive T-Lymphocytes ; CTLA-4 Antigen/genetics ; HIV Infections ; Receptors, Immunologic ; RNA ; T-Lymphocytes ; Programmed Cell Death 1 Receptor/metabolism
Chemical Substances	CTLA-4 Antigen ; CTLA4 protein, human ; Receptors, Immunologic ; RNA (63231-63-0) ; Programmed Cell Death 1 Receptor
Language	English
Publishing date	2022-10-04
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
ISSN	2666-3791
ISSN (online)	2666-3791
DOI	10.1016/j.xcrm.2022.100766
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Article ; Online: Modulation of the CCR5 Receptor/Ligand Axis by Seminal Plasma and the Utility of

Juno, Jennifer A / Wragg, Kathleen M / Kristensen, Anne B / Lee, Wen Shi / Selva, Kevin J / van der Sluis, Renee M / Kelleher, Anthony D / Bavinton, Benjamin R / Grulich, Andrew E / Lewin, Sharon R / Kent, Stephen J / Parsons, Matthew S

Journal of virology

2019 Volume 93, Issue 11

Abstract: Sexual HIV-1 transmission occurs primarily in the presence of semen. Although data from macaque studies suggest that ... ...

Abstract	Sexual HIV-1 transmission occurs primarily in the presence of semen. Although data from macaque studies suggest that CCR5
MeSH term(s)	Animals ; CD4-Positive T-Lymphocytes/immunology ; CD4-Positive T-Lymphocytes/metabolism ; CD8-Positive T-Lymphocytes/immunology ; CD8-Positive T-Lymphocytes/metabolism ; Chemokine CCL5/metabolism ; Chemokines, CC/drug effects ; Chemokines, CC/metabolism ; Disease Models, Animal ; Female ; HIV Infections/immunology ; HIV-1/immunology ; Humans ; Killer Cells, Natural/metabolism ; Macaca ; Macrophage Inflammatory Proteins ; Male ; Receptors, CCR5/metabolism ; Receptors, CCR5/physiology ; Semen/immunology ; Semen/metabolism ; T-Lymphocytes
Chemical Substances	CCL15 protein, human ; CCL5 protein, human ; CCR5 protein, human ; Chemokine CCL5 ; Chemokines, CC ; Macrophage Inflammatory Proteins ; Receptors, CCR5
Language	English
Publishing date	2019-05-15
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.00242-19
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Article ; Online: Editorial: Exploring Novel Approaches to Eliminate HIV Reservoirs to Achieve a Cure for HIV.

van der Sluis, Renée M / Finzi, Andrés / Parsons, Matthew S

Frontiers in cellular and infection microbiology

2021 Volume 11, Page(s) 658848

MeSH term(s)	CD4-Positive T-Lymphocytes ; HIV Infections ; HIV-1 ; Humans ; Virus Latency
Language	English
Publishing date	2021-02-25
Publishing country	Switzerland
Document type	Editorial ; Introductory Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2619676-1
ISSN	2235-2988 ; 2235-2988
ISSN (online)	2235-2988
ISSN	2235-2988
DOI	10.3389/fcimb.2021.658848
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Article ; Online: Antiviral Potential of the Antimicrobial Drug Atovaquone against SARS-CoV-2 and Emerging Variants of Concern.

Carter-Timofte, Madalina Elena / Arulanandam, Rozanne / Kurmasheva, Naziia / Fu, Kathy / Laroche, Geneviève / Taha, Zaid / van der Horst, Demi / Cassin, Lena / van der Sluis, Renée M / Palermo, Enrico / Di Carlo, Daniele / Jacobs, David / Maznyi, Glib / Azad, Taha / Singaravelu, Ragunath / Ren, Fanghui / Hansen, Anne Louise / Idorn, Manja / Holm, Christian K /

Jakobsen, Martin R / van Grevenynghe, Julien / Hiscott, John / Paludan, Søren R / Bell, John C / Seguin, Jean / Sabourin, Luc A / Côté, Marceline / Diallo, Jean-Simon / Alain, Tommy / Olagnier, David

ACS infectious diseases

2021 Volume 7, Issue 11, Page(s) 3034–3051

Abstract: The antimicrobial medication malarone (atovaquone/proguanil) is used as a fixed-dose combination for treating children and adults with uncomplicated malaria or as chemoprophylaxis for preventing malaria in travelers. It is an inexpensive, efficacious, ... ...

Abstract	The antimicrobial medication malarone (atovaquone/proguanil) is used as a fixed-dose combination for treating children and adults with uncomplicated malaria or as chemoprophylaxis for preventing malaria in travelers. It is an inexpensive, efficacious, and safe drug frequently prescribed around the world. Following anecdotal evidence from 17 patients in the provinces of Quebec and Ontario, Canada, suggesting that malarone/atovaquone may present some benefits in protecting against COVID-19, we sought to examine its antiviral potential in limiting the replication of SARS-CoV-2 in cellular models of infection. In VeroE6 expressing human TMPRSS2 and human lung Calu-3 epithelial cells, we show that the active compound atovaquone at micromolar concentrations potently inhibits the replication of SARS-CoV-2 and other variants of concern including the alpha, beta, and delta variants. Importantly, atovaquone retained its full antiviral activity in a primary human airway epithelium cell culture model. Mechanistically, we demonstrate that the atovaquone antiviral activity against SARS-CoV-2 is partially dependent on the expression of TMPRSS2 and that the drug can disrupt the interaction of the spike protein with the viral receptor, ACE2. Additionally, spike-mediated membrane fusion was also reduced in the presence of atovaquone. In the United States, two clinical trials of atovaquone administered alone or in combination with azithromycin were initiated in 2020. While we await the results of these trials, our findings in cellular infection models demonstrate that atovaquone is a potent antiviral FDA-approved drug against SARS-CoV-2 and other variants of concern in vitro.
MeSH term(s)	Antiviral Agents/pharmacology ; Antiviral Agents/therapeutic use ; Atovaquone/pharmacology ; COVID-19 ; Humans ; SARS-CoV-2 ; United States
Chemical Substances	Antiviral Agents ; Atovaquone (Y883P1Z2LT)
Language	English
Publishing date	2021-10-18
Publishing country	United States
Document type	Journal Article
ISSN	2373-8227
ISSN (online)	2373-8227
DOI	10.1021/acsinfecdis.1c00278
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Article ; Online: Plasmacytoid Dendritic Cells as Cell-Based Therapeutics: A Novel Immunotherapy to Treat Human Immunodeficiency Virus Infection?

van der Sluis, Renée M / Egedal, Johanne H / Jakobsen, Martin R

Frontiers in cellular and infection microbiology

2020 Volume 10, Page(s) 249

Abstract: Dendritic cells (DCs) play a critical role in mediating innate and adaptive immune responses. Since their discovery in the late 1970's, DCs have been recognized as the most potent antigen-presenting cells (APCs). DCs have a superior capacity for ... ...

Abstract	Dendritic cells (DCs) play a critical role in mediating innate and adaptive immune responses. Since their discovery in the late 1970's, DCs have been recognized as the most potent antigen-presenting cells (APCs). DCs have a superior capacity for acquiring, processing, and presenting antigens to T cells and they express costimulatory or coinhibitory molecules that determine immune activation or anergy. For these reasons, cell-based therapeutic approaches using DCs have been explored in cancer and infectious diseases but with limited success. In humans, DCs are divided into heterogeneous subsets with distinct characteristics. Two major subsets are CD11c
MeSH term(s)	CD11c Antigen ; Cell- and Tissue-Based Therapy ; Dendritic Cells ; HIV Infections/therapy ; Humans ; Immunotherapy ; Interferon Type I
Chemical Substances	CD11c Antigen ; Interferon Type I
Keywords	covid19
Language	English
Publishing date	2020-05-26
Publishing country	Switzerland
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	2619676-1
ISSN	2235-2988 ; 2235-2988
ISSN (online)	2235-2988
ISSN	2235-2988
DOI	10.3389/fcimb.2020.00249
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Article ; Online: Single cell analysis reveals a subset of cytotoxic-like plasmacytoid dendritic cells in people with HIV-1.

Cham, Lamin B / Gunst, Jesper D / Schleimann, Mariane H / Frattari, Giacomo S / Rosas-Umbert, Miriam / Vibholm, Line K / van der Sluis, Renée M / Jakobsen, Martin R / Olesen, Rikke / Lin, Lin / Tolstrup, Martin / Søgaard, Ole S

iScience

2023 Volume 26, Issue 9, Page(s) 107628

Abstract: Human plasmacytoid dendritic cells (pDCs) play a central role in initiating and activating host immune responses during infection. To understand how the transcriptome of pDCs is impacted by HIV-1 infection and exogenous stimulation, we isolated pDCs from ...

Abstract	Human plasmacytoid dendritic cells (pDCs) play a central role in initiating and activating host immune responses during infection. To understand how the transcriptome of pDCs is impacted by HIV-1 infection and exogenous stimulation, we isolated pDCs from healthy controls, people with HIV-1 (PWH) before and during toll-like receptor 9 (TLR9) agonist treatment and performed single-cell (sc)-RNA sequencing. Our cluster analysis revealed four pDC clusters: pDC1, pDC2, cytotoxic-like pDC and an exhausted pDC cluster. The inducible cytotoxic-like pDC cluster is characterized by high expression of both antiviral and cytotoxic genes. Further analyses confirmed that cytotoxic-like pDCs are distinct from NK and T cells. Cell-cell communication analysis also demonstrated that cytotoxic-like pDCs exhibit similar incoming and outgoing cellular communicating signals as other pDCs. Thus, our study presents a detailed transcriptomic atlas of pDCs and provides new perspectives on the mechanisms of regulation and function of cytotoxic-like pDCs.
Language	English
Publishing date	2023-08-12
Publishing country	United States
Document type	Journal Article
ISSN	2589-0042
ISSN (online)	2589-0042
DOI	10.1016/j.isci.2023.107628
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Article: Plasmacytoid Dendritic Cells as Cell-Based Therapeutics: A Novel Immunotherapy to Treat Human Immunodeficiency Virus Infection?

van der Sluis, Renée M / Egedal, Johanne H / Jakobsen, Martin R

Front Cell Infect Microbiol

Abstract: ... major subsets are CD11c+ myeloid (m)DCs and CD11c- plasmacytoid (p)DCs. pDCs are different from mDCs and ...

Abstract	Dendritic cells (DCs) play a critical role in mediating innate and adaptive immune responses. Since their discovery in the late 1970's, DCs have been recognized as the most potent antigen-presenting cells (APCs). DCs have a superior capacity for acquiring, processing, and presenting antigens to T cells and they express costimulatory or coinhibitory molecules that determine immune activation or anergy. For these reasons, cell-based therapeutic approaches using DCs have been explored in cancer and infectious diseases but with limited success. In humans, DCs are divided into heterogeneous subsets with distinct characteristics. Two major subsets are CD11c+ myeloid (m)DCs and CD11c- plasmacytoid (p)DCs. pDCs are different from mDCs and play an essential role in the innate immune system via the production of type I interferons (IFN). However, pDCs are also able to take-up antigens and effectively cross present them. Given the rarity of pDCs in blood and technical difficulties in obtaining them from human blood samples, the understanding of human pDC biology and their potential in immunotherapeutic approaches (e.g. cell-based vaccines) is limited. However, due to the recent advancements in cell culturing systems that allow for the generation of functional pDCs from CD34+ hematopoietic stem and progenitor cells (HSPC), studying pDCs has become easier. In this mini-review, we hypothesize about the use of pDCs as a cell-based therapy to treat HIV by enhancing anti-HIV-immune responses of the adaptive immune system and enhancing the anti-viral responses of the innate immune system. Additionally, we discuss obstacles to overcome before this approach becomes clinically applicable.
Keywords	covid19
Publisher	WHO
Document type	Article
Note	WHO #Covidence: #32528903
Database	COVID19

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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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Article ; Online: Varied sensitivity to therapy of HIV-1 strains in CD4+ lymphocyte sub-populations upon ART initiation.

Heeregrave, Edwin J / Geels, Mark J / Baan, Elly / van der Sluis, Renee M / Paxton, William A / Pollakis, Georgios

AIDS research and therapy

2010 Volume 7, Page(s) 42

Abstract: Background: Although antiretroviral therapy (ART) has proven its success against HIV-1, the long lifespan of infected cells and viral latency prevent eradication. In this study we analyzed the sensitivity to ART of HIV-1 strains in naïve, central memory ...

Abstract	Background: Although antiretroviral therapy (ART) has proven its success against HIV-1, the long lifespan of infected cells and viral latency prevent eradication. In this study we analyzed the sensitivity to ART of HIV-1 strains in naïve, central memory and effector memory CD4+ lymphocyte subsets. Methods: From five patients cellular HIV-1 infection levels were quantified before and after initiation of therapy (2-5 weeks). Through sequencing the C2V3 region of the HIV-1 gp120 envelope, we studied the effect of short-term therapy on virus variants derived from naïve, central memory and effector memory CD4+ lymphocyte subsets. Results: During short-term ART, HIV-1 infection levels declined in all lymphocyte subsets but not as much as RNA levels in serum. Virus diversity in the naïve and central memory lymphocyte populations remained unchanged, whilst diversity decreased in serum and the effector memory lymphocytes. ART differentially affected the virus populations co-circulating in one individual harboring a dual HIV-1 infection. Changes in V3 charge were found in all individuals after ART initiation with increases within the effector memory subset and decreases found in the naïve cell population. Conclusions: During early ART virus diversity is affected mainly in the serum and effector memory cell compartments. Differential alterations in V3 charge were observed between effector memory and naïve populations. While certain cell populations can be targeted preferentially during early ART, some virus strains demonstrate varied sensitivity to therapy, as shown from studying two strains within a dual HIV-1 infected individual.
Language	English
Publishing date	2010-12-06
Publishing country	England
Document type	Journal Article
ISSN	1742-6405
ISSN (online)	1742-6405
DOI	10.1186/1742-6405-7-42
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