Publications
1.
Fabian Roesmann, Helene Sertznig, Katleen Klaassen, Alexander Wilhelm, Delia Heininger, Stefanie Heß, Carina Elsner, Rolf Marschalek, Mario L Santiago, Stefan Esser, Kathrin Sutter, Ulf Dittmer, Marek Widera
In: J Virol, vol. 98, no. 7, pp. e0053424, 2024, ISSN: 1098 – 5514.
@article{pmid38899932,
title = {The interferon-regulated host factor hnRNPA0 modulates HIV-1 production by interference with LTR activity, mRNA trafficking, and programmed ribosomal frameshifting},
author = {Fabian Roesmann and Helene Sertznig and Katleen Klaassen and Alexander Wilhelm and Delia Heininger and Stefanie Heß and Carina Elsner and Rolf Marschalek and Mario L Santiago and Stefan Esser and Kathrin Sutter and Ulf Dittmer and Marek Widera},
doi = {10.1128/jvi.00534-24},
issn = {1098-5514},
year = {2024},
date = {2024-07-01},
journal = {J Virol},
volume = {98},
number = {7},
pages = {e0053424},
abstract = {The interplay between host factors and viral components impacts viral replication efficiency profoundly. Members of the cellular heterogeneous nuclear ribonucleoprotein family (hnRNPs) have been extensively studied as HIV-1 host dependency factors, but whether they play a role in innate immunity is currently unknown. This study aimed to identify hnRNPA0 as a type I interferon (IFN)-repressed host factor in HIV-1-infected cells. Knockdown of hnRNPA0, a situation that mirrors conditions under IFN stimulation, increased LTR activity, export of unspliced HIV-1 mRNA, viral particle production, and thus, increased infectivity. Conversely, hnRNPA0 overexpression primarily reduced plasmid-driven and integrated HIV-1 long terminal repeat (LTR) activity, significantly decreasing total viral mRNA and protein levels. In addition, high levels of hnRNPA0 significantly reduced the HIV-1 programmed ribosomal frameshifting efficiency, resulting in a shift in the HIV-1 p55/p15 ratio. The HIV-1 alternative splice site usage remained largely unaffected by altered hnRNPA0 levels suggesting that the synergistic inhibition of the LTR activity and viral mRNA transcription, as well as impaired ribosomal frameshifting efficiency, are critical factors for efficient HIV-1 replication regulated by hnRNPA0. The pleiotropic dose-dependent effects under high or low hnRNPA0 levels were further confirmed in HIV-1-infected Jurkat cells. Finally, our study revealed that hnRNPA0 levels in PBMCs were lower in therapy-naive HIV-1-infected individuals compared to healthy controls. Our findings highlight a significant role for hnRNPA0 in HIV-1 replication and suggest that its IFN-I-regulated expression levels are critical for viral fitness allowing replication in an antiviral environment.IMPORTANCERNA-binding proteins, in particular, heterogeneous nuclear ribonucleoproteins (hnRNPs), have been extensively studied. Some act as host dependency factors for HIV-1 since they are involved in multiple cellular gene expression processes. Our study revealed hnRNPA0 as an IFN-regulated host factor, that is differently expressed after IFN-I treatment in HIV-1 target cells and lower expressed in therapy-naïve HIV-1-infected individuals. Our findings demonstrate the significant pleiotropic role of hnRNPA0 in viral replication: In high concentrations, hnRNPA0 limits viral replication by negatively regulating Tat-LTR transcription, retaining unspliced mRNA in the nucleus, and significantly impairing programmed ribosomal frameshifting. Low hnRNPA0 levels as observed in IFN-treated THP-1 cells, particularly facilitate HIV LTR activity and unspliced mRNA export, suggesting a role in innate immunity in favor of HIV replication. Understanding the mode of action between hnRNPA0 and HIV-1 gene expression might help to identify novel therapeutically strategies against HIV-1 and other viruses.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
The interplay between host factors and viral components impacts viral replication efficiency profoundly. Members of the cellular heterogeneous nuclear ribonucleoprotein family (hnRNPs) have been extensively studied as HIV‑1 host dependency factors, but whether they play a role in innate immunity is currently unknown. This study aimed to identify hnRNPA0 as a type I interferon (IFN)-repressed host factor in HIV-1-infected cells. Knockdown of hnRNPA0, a situation that mirrors conditions under IFN stimulation, increased LTR activity, export of unspliced HIV‑1 mRNA, viral particle production, and thus, increased infectivity. Conversely, hnRNPA0 overexpression primarily reduced plasmid-driven and integrated HIV‑1 long terminal repeat (LTR) activity, significantly decreasing total viral mRNA and protein levels. In addition, high levels of hnRNPA0 significantly reduced the HIV‑1 programmed ribosomal frameshifting efficiency, resulting in a shift in the HIV‑1 p55/p15 ratio. The HIV‑1 alternative splice site usage remained largely unaffected by altered hnRNPA0 levels suggesting that the synergistic inhibition of the LTR activity and viral mRNA transcription, as well as impaired ribosomal frameshifting efficiency, are critical factors for efficient HIV‑1 replication regulated by hnRNPA0. The pleiotropic dose-dependent effects under high or low hnRNPA0 levels were further confirmed in HIV-1-infected Jurkat cells. Finally, our study revealed that hnRNPA0 levels in PBMCs were lower in therapy-naive HIV-1-infected individuals compared to healthy controls. Our findings highlight a significant role for hnRNPA0 in HIV‑1 replication and suggest that its IFN-I-regulated expression levels are critical for viral fitness allowing replication in an antiviral environment.IMPORTANCERNA-binding proteins, in particular, heterogeneous nuclear ribonucleoproteins (hnRNPs), have been extensively studied. Some act as host dependency factors for HIV‑1 since they are involved in multiple cellular gene expression processes. Our study revealed hnRNPA0 as an IFN-regulated host factor, that is differently expressed after IFN‑I treatment in HIV‑1 target cells and lower expressed in therapy-naïve HIV-1-infected individuals. Our findings demonstrate the significant pleiotropic role of hnRNPA0 in viral replication: In high concentrations, hnRNPA0 limits viral replication by negatively regulating Tat-LTR transcription, retaining unspliced mRNA in the nucleus, and significantly impairing programmed ribosomal frameshifting. Low hnRNPA0 levels as observed in IFN-treated THP‑1 cells, particularly facilitate HIV LTR activity and unspliced mRNA export, suggesting a role in innate immunity in favor of HIV replication. Understanding the mode of action between hnRNPA0 and HIV‑1 gene expression might help to identify novel therapeutically strategies against HIV‑1 and other viruses.
2.
Fabian Roesmann, Lisa Müller, Katleen Klaassen, Stefanie Heß, Marek Widera
Interferon-Regulated Expression of Cellular Splicing Factors Modulates Multiple Levels of HIV‑1 Gene Expression and Replication Journal Article
In: Viruses, vol. 16, no. 6, 2024, ISSN: 1999 – 4915.
@article{pmid38932230,
title = {Interferon-Regulated Expression of Cellular Splicing Factors Modulates Multiple Levels of HIV-1 Gene Expression and Replication},
author = {Fabian Roesmann and Lisa Müller and Katleen Klaassen and Stefanie Heß and Marek Widera},
doi = {10.3390/v16060938},
issn = {1999-4915},
year = {2024},
date = {2024-06-01},
journal = {Viruses},
volume = {16},
number = {6},
abstract = {Type I interferons (IFN-Is) are pivotal in innate immunity against human immunodeficiency virus I (HIV-1) by eliciting the expression of IFN-stimulated genes (ISGs), which encompass potent host restriction factors. While ISGs restrict the viral replication within the host cell by targeting various stages of the viral life cycle, the lesser-known IFN-repressed genes (IRepGs), including RNA-binding proteins (RBPs), affect the viral replication by altering the expression of the host dependency factors that are essential for efficient HIV-1 gene expression. Both the host restriction and dependency factors determine the viral replication efficiency; however, the understanding of the IRepGs implicated in HIV-1 infection remains greatly limited at present. This review provides a comprehensive overview of the current understanding regarding the impact of the RNA-binding protein families, specifically the two families of splicing-associated proteins SRSF and hnRNP, on HIV-1 gene expression and viral replication. Since the recent findings show specifically that SRSF1 and hnRNP A0 are regulated by IFN-I in various cell lines and primary cells, including intestinal lamina propria mononuclear cells (LPMCs) and peripheral blood mononuclear cells (PBMCs), we particularly discuss their role in the context of the innate immunity affecting HIV-1 replication.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Type I interferons (IFN-Is) are pivotal in innate immunity against human immunodeficiency virus I (HIV‑1) by eliciting the expression of IFN-stimulated genes (ISGs), which encompass potent host restriction factors. While ISGs restrict the viral replication within the host cell by targeting various stages of the viral life cycle, the lesser-known IFN-repressed genes (IRepGs), including RNA-binding proteins (RBPs), affect the viral replication by altering the expression of the host dependency factors that are essential for efficient HIV‑1 gene expression. Both the host restriction and dependency factors determine the viral replication efficiency; however, the understanding of the IRepGs implicated in HIV‑1 infection remains greatly limited at present. This review provides a comprehensive overview of the current understanding regarding the impact of the RNA-binding protein families, specifically the two families of splicing-associated proteins SRSF and hnRNP, on HIV‑1 gene expression and viral replication. Since the recent findings show specifically that SRSF1 and hnRNP A0 are regulated by IFN‑I in various cell lines and primary cells, including intestinal lamina propria mononuclear cells (LPMCs) and peripheral blood mononuclear cells (PBMCs), we particularly discuss their role in the context of the innate immunity affecting HIV‑1 replication.
3.
Chaohui Lin, Edmund Osei Kuffour, Nina V Fuchs, Christoph G W Gertzen, Jesko Kaiser, Maximilian Hirschenberger, Xiao Tang, Haifeng C Xu, Oliver Michel, Ronny Tao, Alexandra Haase, Ulrich Martin, Thomas Kurz, Ingo Drexler, Boris Görg, Philipp A Lang, Tom Luedde, Konstantin M J Sparrer, Holger Gohlke, Renate König, Carsten Münk
Regulation of STING activity in DNA sensing by ISG15 modification Journal Article
In: Cell Rep, vol. 42, no. 11, pp. 113277, 2023, ISSN: 2211 – 1247.
@article{pmid37864791,
title = {Regulation of STING activity in DNA sensing by ISG15 modification},
author = {Chaohui Lin and Edmund Osei Kuffour and Nina V Fuchs and Christoph G W Gertzen and Jesko Kaiser and Maximilian Hirschenberger and Xiao Tang and Haifeng C Xu and Oliver Michel and Ronny Tao and Alexandra Haase and Ulrich Martin and Thomas Kurz and Ingo Drexler and Boris Görg and Philipp A Lang and Tom Luedde and Konstantin M J Sparrer and Holger Gohlke and Renate König and Carsten Münk},
doi = {10.1016/j.celrep.2023.113277},
issn = {2211-1247},
year = {2023},
date = {2023-10-01},
journal = {Cell Rep},
volume = {42},
number = {11},
pages = {113277},
abstract = {Sensing of human immunodeficiency virus type 1 (HIV-1) DNA is mediated by the cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) signaling axis. Signal transduction and regulation of this cascade is achieved by post-translational modifications. Here we show that cGAS-STING-dependent HIV-1 sensing requires interferon-stimulated gene 15 (ISG15). ISG15 deficiency inhibits STING-dependent sensing of HIV-1 and STING agonist-induced antiviral response. Upon external stimuli, STING undergoes ISGylation at residues K224, K236, K289, K347, K338, and K370. Inhibition of STING ISGylation at K289 suppresses STING-mediated type Ⅰ interferon induction by inhibiting its oligomerization. Of note, removal of STING ISGylation alleviates gain-of-function phenotype in STING-associated vasculopathy with onset in infancy (SAVI). Molecular modeling suggests that ISGylation of K289 is an important regulator of oligomerization. Taken together, our data demonstrate that ISGylation at K289 is crucial for STING activation and represents an important regulatory step in DNA sensing of viruses and autoimmune responses.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Sensing of human immunodeficiency virus type 1 (HIV‑1) DNA is mediated by the cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) signaling axis. Signal transduction and regulation of this cascade is achieved by post-translational modifications. Here we show that cGAS-STING-dependent HIV‑1 sensing requires interferon-stimulated gene 15 (ISG15). ISG15 deficiency inhibits STING-dependent sensing of HIV‑1 and STING agonist-induced antiviral response. Upon external stimuli, STING undergoes ISGylation at residues K224, K236, K289, K347, K338, and K370. Inhibition of STING ISGylation at K289 suppresses STING-mediated type Ⅰ interferon induction by inhibiting its oligomerization. Of note, removal of STING ISGylation alleviates gain-of-function phenotype in STING-associated vasculopathy with onset in infancy (SAVI). Molecular modeling suggests that ISGylation of K289 is an important regulator of oligomerization. Taken together, our data demonstrate that ISGylation at K289 is crucial for STING activation and represents an important regulatory step in DNA sensing of viruses and autoimmune responses.
4.
Moritz Schüssler, Kerstin Schott, Nina Verena Fuchs, Adrian Oo, Morssal Zahadi, Paula Rauch, Baek Kim, Renate König
2023.
@misc{pmid37662193,
title = {Gene editing of in macrophage-like cells reveals complex relationships between SAMHD1 phospho-regulation, HIV-1 restriction and cellular dNTP levels},
author = {Moritz Schüssler and Kerstin Schott and Nina Verena Fuchs and Adrian Oo and Morssal Zahadi and Paula Rauch and Baek Kim and Renate König},
doi = {10.1101/2023.08.24.554731},
year = {2023},
date = {2023-08-01},
journal = {bioRxiv},
abstract = {Sterile α motif (SAM) and HD domain-containing protein 1 (SAMHD1) is a dNTP triphosphate triphosphohydrolase (dNTPase) and a potent restriction factor for immunodeficiency virus 1 (HIV-1), active in myeloid and resting CD4 T cells. The anti-viral activity of SAMHD1 is regulated by dephosphorylation of the residue T592. However, the impact of T592 phosphorylation on dNTPase activity is still under debate. Whether additional cellular functions of SAMHD1 impact anti-viral restriction is not completely understood. We report BLaER1 cells as a novel human macrophage HIV-1 infection model combined with CRISPR/Cas9 knock-in (KI) introducing specific mutations into the locus to study mutations in a physiological context. Transdifferentiated BLaER1 cells harbor active dephosphorylated SAMHD1 that blocks HIV-1 reporter virus infection. As expected, homozygous T592E mutation, but not T592A, relieved a block to HIV-1 reverse transcription. Co-delivery of VLP-Vpx to SAMHD1 T592E KI mutant cells did not further enhance HIV-1 infection indicating the absence of an additional SAMHD1-mediated antiviral activity independent of T592 de-phosphorylation. T592E KI cells retained dNTP levels similar to WT cells indicating uncoupling of anti-viral and dNTPase activity of SAMHD1. The integrity of the catalytic site in SAMHD1 was critical for anti-viral activity, yet poor correlation of HIV-1 restriction and global cellular dNTP levels was observed in cells harboring catalytic core mutations. Together, we emphasize the complexity of the relationship between HIV-1 restriction, SAMHD1 enzymatic function and T592 phospho-regulation and provide novel tools for investigation in an endogenous and physiological context.},
keywords = {},
pubstate = {published},
tppubtype = {misc}
}
Sterile α motif (SAM) and HD domain-containing protein 1 (SAMHD1) is a dNTP triphosphate triphosphohydrolase (dNTPase) and a potent restriction factor for immunodeficiency virus 1 (HIV‑1), active in myeloid and resting CD4 T cells. The anti-viral activity of SAMHD1 is regulated by dephosphorylation of the residue T592. However, the impact of T592 phosphorylation on dNTPase activity is still under debate. Whether additional cellular functions of SAMHD1 impact anti-viral restriction is not completely understood. We report BLaER1 cells as a novel human macrophage HIV‑1 infection model combined with CRISPR/Cas9 knock-in (KI) introducing specific mutations into the locus to study mutations in a physiological context. Transdifferentiated BLaER1 cells harbor active dephosphorylated SAMHD1 that blocks HIV‑1 reporter virus infection. As expected, homozygous T592E mutation, but not T592A, relieved a block to HIV‑1 reverse transcription. Co-delivery of VLP-Vpx to SAMHD1 T592E KI mutant cells did not further enhance HIV‑1 infection indicating the absence of an additional SAMHD1-mediated antiviral activity independent of T592 de-phosphorylation. T592E KI cells retained dNTP levels similar to WT cells indicating uncoupling of anti-viral and dNTPase activity of SAMHD1. The integrity of the catalytic site in SAMHD1 was critical for anti-viral activity, yet poor correlation of HIV‑1 restriction and global cellular dNTP levels was observed in cells harboring catalytic core mutations. Together, we emphasize the complexity of the relationship between HIV‑1 restriction, SAMHD1 enzymatic function and T592 phospho-regulation and provide novel tools for investigation in an endogenous and physiological context.
5.
Hussein Al-Shehabi, Norbert Bannert
PERV induces CXCL10 in human monocytes and monocyte-derived primary cells. Journal Article
In: online ahead of print, 2022, ISSN: 1423 – 0100.
@article{AlShehabi2022,
title = {PERV induces CXCL10 in human monocytes and monocyte-derived primary cells.},
author = {Hussein Al-Shehabi and Norbert Bannert},
doi = {10.1159/000527074},
issn = {1423-0100},
year = {2022},
date = {2022-11-16},
urldate = {2022-11-16},
journal = {online ahead of print},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
6.
Thomas A Packard, Roland Schwarzer, Eytan Herzig, Deepashri Rao, Xiaoyu Luo, Johanne H Egedal, Feng Hsiao, Marek Widera, Judd F Hultquist, Zachary W Grimmett, Ronald J Messer, Nevan J Krogan, Steven G Deeks, Nadia R Roan, Ulf Dittmer, Kim J Hasenkrug, Warner C Greene
CCL2: a Chemokine Potentially Promoting Early Seeding of the Latent HIV Reservoir Journal Article
In: mBio, vol. 13, no. 5, pp. e0189122, 2022, ISSN: 2150 – 7511.
@article{pmid36073812,
title = {CCL2: a Chemokine Potentially Promoting Early Seeding of the Latent HIV Reservoir},
author = {Thomas A Packard and Roland Schwarzer and Eytan Herzig and Deepashri Rao and Xiaoyu Luo and Johanne H Egedal and Feng Hsiao and Marek Widera and Judd F Hultquist and Zachary W Grimmett and Ronald J Messer and Nevan J Krogan and Steven G Deeks and Nadia R Roan and Ulf Dittmer and Kim J Hasenkrug and Warner C Greene},
doi = {10.1128/mbio.01891-22},
issn = {2150-7511},
year = {2022},
date = {2022-10-01},
journal = {mBio},
volume = {13},
number = {5},
pages = {e0189122},
abstract = {HIV infects long-lived CD4 memory T cells, establishing a latent viral reservoir that necessitates lifelong antiretroviral therapy (ART). How this reservoir is formed so quickly after infection remains unclear. We now show the innate inflammatory response to HIV infection results in CCL2 chemokine release, leading to recruitment of cells expressing the CCR2 receptor, including a subset of central memory CD4 T cells. Supporting a role for the CCL2/CCR2 axis in rapid reservoir formation, we find (i) treatment of humanized mice with anti-CCL2 antibodies during early HIV infection decreases reservoir seeding and preserves CCR2/5 cells and (ii) CCR2/5 cells from the blood of HIV-infected individuals on long-term ART contain significantly more integrated provirus than CCR2/5-negative memory or naive cells. Together, these studies support a model where the host's innate inflammatory response to HIV infection, including CCL2 production, leads to the recruitment of CCR2/5 central memory CD4 T cells to zones of virus-associated inflammation, likely contributing to rapid formation of the latent HIV reservoir. There are currently over 35 million people living with HIV worldwide, and we still have no vaccine or scalable cure. One of the difficulties with HIV is its ability to rapidly establish a viral reservoir in lymphoid tissues that allows it to elude antivirals and the immune system. Thus, it is important to understand how HIV accomplishes this so we can develop preventive strategies. Our current results show that an early inflammatory response to HIV infection includes production of the chemokine CCL2, which recruits a unique subset of CCR2/5 CD4 T cells that become infected and form a significant reservoir for latent infection. Furthermore, we show that blockade of CCL2 in humanized mice significantly reduces persistent HIV infection. This information is relevant to the development of therapeutics to prevent and/or treat chronic HIV infections.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
HIV infects long-lived CD4 memory T cells, establishing a latent viral reservoir that necessitates lifelong antiretroviral therapy (ART). How this reservoir is formed so quickly after infection remains unclear. We now show the innate inflammatory response to HIV infection results in CCL2 chemokine release, leading to recruitment of cells expressing the CCR2 receptor, including a subset of central memory CD4 T cells. Supporting a role for the CCL2/CCR2 axis in rapid reservoir formation, we find (i) treatment of humanized mice with anti-CCL2 antibodies during early HIV infection decreases reservoir seeding and preserves CCR2/5 cells and (ii) CCR2/5 cells from the blood of HIV-infected individuals on long-term ART contain significantly more integrated provirus than CCR2/5‑negative memory or naive cells. Together, these studies support a model where the host’s innate inflammatory response to HIV infection, including CCL2 production, leads to the recruitment of CCR2/5 central memory CD4 T cells to zones of virus-associated inflammation, likely contributing to rapid formation of the latent HIV reservoir. There are currently over 35 million people living with HIV worldwide, and we still have no vaccine or scalable cure. One of the difficulties with HIV is its ability to rapidly establish a viral reservoir in lymphoid tissues that allows it to elude antivirals and the immune system. Thus, it is important to understand how HIV accomplishes this so we can develop preventive strategies. Our current results show that an early inflammatory response to HIV infection includes production of the chemokine CCL2, which recruits a unique subset of CCR2/5 CD4 T cells that become infected and form a significant reservoir for latent infection. Furthermore, we show that blockade of CCL2 in humanized mice significantly reduces persistent HIV infection. This information is relevant to the development of therapeutics to prevent and/or treat chronic HIV infections.
7.
Helene Sertznig, Fabian Roesmann, Alexander Wilhelm, Delia Heininger, Barbara Bleekmann, Carina Elsner, Mario Santiago, Jonas Schuhenn, Zehra Karakoese, Yvonne Benatzy, Ryan Snodgrass, Stefan Esser, Kathrin Sutter, Ulf Dittmer, Marek Widera
SRSF1 acts as an IFN-I-regulated cellular dependency factor decisively affecting HIV‑1 post-integration steps Journal Article
In: Front Immunol, vol. 13, pp. 935800, 2022, ISSN: 1664 – 3224.
@article{pmid36458014,
title = {SRSF1 acts as an IFN-I-regulated cellular dependency factor decisively affecting HIV-1 post-integration steps},
author = {Helene Sertznig and Fabian Roesmann and Alexander Wilhelm and Delia Heininger and Barbara Bleekmann and Carina Elsner and Mario Santiago and Jonas Schuhenn and Zehra Karakoese and Yvonne Benatzy and Ryan Snodgrass and Stefan Esser and Kathrin Sutter and Ulf Dittmer and Marek Widera},
doi = {10.3389/fimmu.2022.935800},
issn = {1664-3224},
year = {2022},
date = {2022-01-01},
journal = {Front Immunol},
volume = {13},
pages = {935800},
abstract = {Efficient HIV-1 replication depends on balanced levels of host cell components including cellular splicing factors as the family of serine/arginine-rich splicing factors (SRSF, 1-10). Type I interferons (IFN-I) play a crucial role in the innate immunity against HIV-1 by inducing the expression of IFN-stimulated genes (ISGs) including potent host restriction factors. The less well known IFN-repressed genes (IRepGs) might additionally affect viral replication by downregulating host dependency factors that are essential for the viral life cycle; however, so far, the knowledge about IRepGs involved in HIV-1 infection is very limited. In this work, we could demonstrate that HIV-1 infection and the associated ISG induction correlated with low SRSF1 levels in intestinal lamina propria mononuclear cells (LPMCs) and peripheral blood mononuclear cells (PBMCs) during acute and chronic HIV-1 infection. In HIV-1-susceptible cell lines as well as primary monocyte-derived macrophages (MDMs), expression levels of SRSF1 were transiently repressed upon treatment with specific IFNα subtypes in vitro. Mechanically, 4sU labeling of newly transcribed mRNAs revealed that IFN-mediated SRSF1 repression is regulated on early RNA level. SRSF1 knockdown led to an increase in total viral RNA levels, but the relative proportion of the HIV-1 viral infectivity factor (Vif) coding transcripts, which is essential to counteract APOBEC3G-mediated host restriction, was significantly reduced. In the presence of high APOBEC3G levels, however, increased LTR activity upon SRSF1 knockdown facilitated the overall replication, despite decreased vif mRNA levels. In contrast, SRSF1 overexpression significantly impaired HIV-1 post-integration steps including LTR transcription, alternative splice site usage, and virus particle production. Since balanced SRSF1 levels are crucial for efficient viral replication, our data highlight the so far undescribed role of SRSF1 acting as an IFN-modulated cellular dependency factor decisively regulating HIV-1 post-integration steps.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Efficient HIV‑1 replication depends on balanced levels of host cell components including cellular splicing factors as the family of serine/arginine-rich splicing factors (SRSF, 1 – 10). Type I interferons (IFN‑I) play a crucial role in the innate immunity against HIV‑1 by inducing the expression of IFN-stimulated genes (ISGs) including potent host restriction factors. The less well known IFN-repressed genes (IRepGs) might additionally affect viral replication by downregulating host dependency factors that are essential for the viral life cycle; however, so far, the knowledge about IRepGs involved in HIV‑1 infection is very limited. In this work, we could demonstrate that HIV‑1 infection and the associated ISG induction correlated with low SRSF1 levels in intestinal lamina propria mononuclear cells (LPMCs) and peripheral blood mononuclear cells (PBMCs) during acute and chronic HIV‑1 infection. In HIV-1-susceptible cell lines as well as primary monocyte-derived macrophages (MDMs), expression levels of SRSF1 were transiently repressed upon treatment with specific IFNα subtypes in vitro. Mechanically, 4sU labeling of newly transcribed mRNAs revealed that IFN-mediated SRSF1 repression is regulated on early RNA level. SRSF1 knockdown led to an increase in total viral RNA levels, but the relative proportion of the HIV‑1 viral infectivity factor (Vif) coding transcripts, which is essential to counteract APOBEC3G-mediated host restriction, was significantly reduced. In the presence of high APOBEC3G levels, however, increased LTR activity upon SRSF1 knockdown facilitated the overall replication, despite decreased vif mRNA levels. In contrast, SRSF1 overexpression significantly impaired HIV‑1 post-integration steps including LTR transcription, alternative splice site usage, and virus particle production. Since balanced SRSF1 levels are crucial for efficient viral replication, our data highlight the so far undescribed role of SRSF1 acting as an IFN-modulated cellular dependency factor decisively regulating HIV‑1 post-integration steps.
8.
Matteo Bosso, Christina M. Stürzel, Dorota Kmiec, Smitha Srinivasachar Badarinarayan, Elisabeth Braun, Jumpei Ito, Kei Sato, Beatrice H. Hahn, Konstantin M. J. Sparrer, Daniel Sauter, Frank Kirchhoff
An additional NF-κB site allows HIV‑1 subtype C to evade restriction by nuclear PYHIN proteins Journal Article
In: Cell Reports, vol. 36, no. 12, pp. 109735, 2021.
@article{Bosso2021,
title = {An additional NF-κB site allows HIV-1 subtype C to evade restriction by nuclear PYHIN proteins},
author = {Matteo Bosso and Christina M. Stürzel and Dorota Kmiec and Smitha Srinivasachar Badarinarayan and Elisabeth Braun and Jumpei Ito and Kei Sato and Beatrice H. Hahn and Konstantin M. J. Sparrer and Daniel Sauter and Frank Kirchhoff},
doi = {10.1016/j.celrep.2021.109735},
year = {2021},
date = {2021-09-01},
urldate = {2021-09-01},
journal = {Cell Reports},
volume = {36},
number = {12},
pages = {109735},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
9.
Caterina Prelli Bozzo, Rayhane Nchioua, Meta Volcic, Lennart Koepke, Jana Krüger, Desiree Schütz, Sandra Heller, Christina M. Stürzel, Dorota Kmiec, Carina Conzelmann, Janis Müller, Fabian Zech, Elisabeth Braun, Rüdiger Groß, Lukas Wettstein, Tatjana Weil, Johanna Weiß, Federica Diofano, Armando A. Rodríguez Alfonso, Sebastian Wiese, Daniel Sauter, Jan Münch, Christine Goffinet, Alberto Catanese, Michael Schön, Tobias M. Boeckers, Steffen Stenger, Kei Sato, Steffen Just, Alexander Kleger, Konstantin M. J. Sparrer, Frank Kirchhoff
IFITM proteins promote SARS-CoV‑2 infection and are targets for virus inhibition in vitro Journal Article
In: Nature Communications, vol. 12, no. 1, pp. 4584, 2021.
@article{Bozzo2021,
title = {IFITM proteins promote SARS-CoV-2 infection and are targets for virus inhibition in vitro},
author = {Caterina Prelli Bozzo and Rayhane Nchioua and Meta Volcic and Lennart Koepke and Jana Krüger and Desiree Schütz and Sandra Heller and Christina M. Stürzel and Dorota Kmiec and Carina Conzelmann and Janis Müller and Fabian Zech and Elisabeth Braun and Rüdiger Groß and Lukas Wettstein and Tatjana Weil and Johanna Weiß and Federica Diofano and Armando A. Rodríguez Alfonso and Sebastian Wiese and Daniel Sauter and Jan Münch and Christine Goffinet and Alberto Catanese and Michael Schön and Tobias M. Boeckers and Steffen Stenger and Kei Sato and Steffen Just and Alexander Kleger and Konstantin M. J. Sparrer and Frank Kirchhoff},
doi = {10.1038/s41467-021-24817-y},
year = {2021},
date = {2021-07-01},
journal = {Nature Communications},
volume = {12},
number = {1},
pages = {4584},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
10.
Smitha Srinivasachar Badarinarayan, Daniel Sauter
Switching Sides: How Endogenous Retroviruses Protect Us from Viral Infections Journal Article
In: Journal of Virology, vol. 95, no. 12, pp. e02299-20, 2021.
@article{Badarinarayan2021,
title = {Switching Sides: How Endogenous Retroviruses Protect Us from Viral Infections},
author = {Smitha Srinivasachar Badarinarayan and Daniel Sauter},
doi = {10.1128/jvi.02299-20},
year = {2021},
date = {2021-05-01},
journal = {Journal of Virology},
volume = {95},
number = {12},
pages = {e02299-20},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
11.
Manuel Hayn, Maximilian Hirschenberger, Lennart Koepke, Rayhane Nchioua, Jan Hendrik Straub, Susanne Klute, Victoria Hunszinger, Fabian Zech, Caterina Prelli Bozzo, Wasim Aftab, Maria Hønholt Christensen, Carina Conzelmann, Janis Alexander Müller, Smitha Srinivasachar Badarinarayan, Christina Martina Stürzel, Ignasi Forne, Steffen Stenger, Karl-Klaus Conzelmann, Jan Münch, Florian Ingo Schmidt, Daniel Sauter, Axel Imhof, Frank Kirchhoff, Konstantin Maria Johannes Sparrer
Systematic functional analysis of SARS-CoV‑2 proteins uncovers viral innate immune antagonists and remaining vulnerabilities Journal Article
In: Cell Reports, vol. 35, no. 7, pp. 109126, 2021.
@article{Hayn2021,
title = {Systematic functional analysis of SARS-CoV-2 proteins uncovers viral innate immune antagonists and remaining vulnerabilities},
author = {Manuel Hayn and Maximilian Hirschenberger and Lennart Koepke and Rayhane Nchioua and Jan Hendrik Straub and Susanne Klute and Victoria Hunszinger and Fabian Zech and Caterina Prelli Bozzo and Wasim Aftab and Maria Hønholt Christensen and Carina Conzelmann and Janis Alexander Müller and Smitha Srinivasachar Badarinarayan and Christina Martina Stürzel and Ignasi Forne and Steffen Stenger and Karl-Klaus Conzelmann and Jan Münch and Florian Ingo Schmidt and Daniel Sauter and Axel Imhof and Frank Kirchhoff and Konstantin Maria Johannes Sparrer},
doi = {10.1016/j.celrep.2021.109126},
year = {2021},
date = {2021-05-01},
journal = {Cell Reports},
volume = {35},
number = {7},
pages = {109126},
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12.
Wen Cui, Elisabeth Braun, Wei Wang, Jinhong Tang, Yanyan Zheng, Benjamin Slater, Na Li, Cheng Chen, Qingxiang Liu, Bin Wang, Xiu Li, Yinkai Duan, Yunjie Xiao, Ruijiao Ti, Dominik Hotter, Xiaoyun Ji, Lei Zhang, Jun Cui, Yong Xiong, Daniel Sauter, Zefang Wang, Frank Kirchhoff, Haitao Yang
Structural basis for GTP-induced dimerization and antiviral function of guanylate-binding proteins Journal Article
In: Proceedings of the National Academy of Sciences (PNAS) of the USA, vol. 118, no. 15, pp. e2022269118, 2021.
@article{Cui2021,
title = {Structural basis for GTP-induced dimerization and antiviral function of guanylate-binding proteins},
author = {Wen Cui and Elisabeth Braun and Wei Wang and Jinhong Tang and Yanyan Zheng and Benjamin Slater and Na Li and Cheng Chen and Qingxiang Liu and Bin Wang and Xiu Li and Yinkai Duan and Yunjie Xiao and Ruijiao Ti and Dominik Hotter and Xiaoyun Ji and Lei Zhang and Jun Cui and Yong Xiong and Daniel Sauter and Zefang Wang and Frank Kirchhoff and Haitao Yang},
doi = {10.1073/pnas.2022269118},
year = {2021},
date = {2021-04-01},
journal = {Proceedings of the National Academy of Sciences (PNAS) of the USA},
volume = {118},
number = {15},
pages = {e2022269118},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
13.
Virginia Pierini, Lara Gallucci, Christina M. Stürzel, Frank Kirchhoff, Oliver T. Fackler
SERINC5 Can Enhance Proinflammatory Cytokine Production by Primary Human Myeloid Cells in Response to Challenge with HIV‑1 Particles Journal Article
In: Journal of Virology, vol. 95, no. 9, pp. e02372-20, 2021.
@article{Pierini2021,
title = {SERINC5 Can Enhance Proinflammatory Cytokine Production by Primary Human Myeloid Cells in Response to Challenge with HIV-1 Particles},
author = {Virginia Pierini and Lara Gallucci and Christina M. Stürzel and Frank Kirchhoff and Oliver T. Fackler},
doi = {10.1128/jvi.02372-20},
year = {2021},
date = {2021-04-01},
journal = {Journal of Virology},
volume = {95},
number = {9},
pages = {e02372-20},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
14.
Renate König, Carsten Münk
Special Issue: “Innate Immune Sensing of Viruses and Viral Evasion” Journal Article
In: Viruses, vol. 13, no. 4, pp. 567, 2021.
@article{Koenig2021,
title = {Special Issue: "Innate Immune Sensing of Viruses and Viral Evasion"},
author = {Renate König and Carsten Münk},
doi = {10.3390/v13040567},
year = {2021},
date = {2021-03-01},
journal = {Viruses},
volume = {13},
number = {4},
pages = {567},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
15.
Oya Cingöz, Nicolas D. Arnow, Mireia Puig Torrents, Norbert Bannert
Vpx enhances innate immune responses independently of SAMHD1 during HIV‑1 infection Journal Article
In: Retrovirology, vol. 18, no. 1, pp. 4, 2021.
@article{Cingoez2021,
title = {Vpx enhances innate immune responses independently of SAMHD1 during HIV-1 infection},
author = {Oya Cingöz and Nicolas D. Arnow and Mireia Puig Torrents and Norbert Bannert},
doi = {10.1186/s12977-021-00548-2},
year = {2021},
date = {2021-02-01},
journal = {Retrovirology},
volume = {18},
number = {1},
pages = {4},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
16.
Lisa Marie Kaiser, Mirja Harms, Daniel Sauter, Vijay P. S. Rawat, Mirco Glitscher, Eberhard Hildt, Daniel Tews, Zachary Hunter, Jan Münch, Christian Buske
Targeting of CXCR4 by the Naturally Occurring CXCR4 Antagonist EPI-X4 in Waldenström’s Macroglobulinemia Journal Article
In: Cancers (Basel), vol. 13, no. 4, pp. 826, 2021.
@article{Kaiser2021,
title = {Targeting of CXCR4 by the Naturally Occurring CXCR4 Antagonist EPI-X4 in Waldenström's Macroglobulinemia},
author = {Lisa Marie Kaiser and Mirja Harms and Daniel Sauter and Vijay P. S. Rawat and Mirco Glitscher and Eberhard Hildt and Daniel Tews and Zachary Hunter and Jan Münch and Christian Buske},
doi = {10.3390/cancers13040826},
year = {2021},
date = {2021-02-01},
journal = {Cancers (Basel)},
volume = {13},
number = {4},
pages = {826},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
17.
Daniel Sauter, Frank Kirchhoff
Evolutionary conflicts and adverse effects of antiviral factors Journal Article
In: eLife, vol. 10, pp. e65243, 2021.
@article{Sauter2021,
title = {Evolutionary conflicts and adverse effects of antiviral factors},
author = {Daniel Sauter and Frank Kirchhoff},
doi = {10.7554/elife.65243},
year = {2021},
date = {2021-01-01},
journal = {eLife},
volume = {10},
pages = {e65243},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
18.
Sheetal Kaw, Swetha Ananth, Nikolaos Tsopoulidis, Katharina Morath, Bahar M Coban, Ralph Hohenberger, Olcay C Bulut, Florian Klein, Bettina Stolp, Oliver T Fackler
HIV‑1 infection of CD4 T cells impairs antigen-specific B cell function Journal Article
In: The EMBO Journal, vol. 39, no. 24, pp. e105594, 2020.
@article{Kaw2020,
title = {HIV-1 infection of CD4 T cells impairs antigen-specific B cell function},
author = {Sheetal Kaw and Swetha Ananth and Nikolaos Tsopoulidis and Katharina Morath and Bahar M Coban and Ralph Hohenberger and Olcay C Bulut and Florian Klein and Bettina Stolp and Oliver T Fackler},
doi = {10.15252/embj.2020105594},
year = {2020},
date = {2020-11-01},
journal = {The EMBO Journal},
volume = {39},
number = {24},
pages = {e105594},
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pubstate = {published},
tppubtype = {article}
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19.
Smitha Srinivasachar Badarinarayan, Irina Shcherbakova, Simon Langer, Lennart Koepke, Andrea Preising, Dominik Hotter, Frank Kirchhoff, Konstantin M J Sparrer, Gunnar Schotta, Daniel Sauter
HIV‑1 infection activates endogenous retroviral promoters regulating antiviral gene expression Journal Article
In: Nucleic Acids Research, vol. 48, no. 19, pp. 10890 – 10908, 2020.
@article{Badarinarayan2020,
title = {HIV-1 infection activates endogenous retroviral promoters regulating antiviral gene expression},
author = {Smitha Srinivasachar Badarinarayan and Irina Shcherbakova and Simon Langer and Lennart Koepke and Andrea Preising and Dominik Hotter and Frank Kirchhoff and Konstantin M J Sparrer and Gunnar Schotta and Daniel Sauter},
doi = {10.1093/nar/gkaa832},
year = {2020},
date = {2020-10-01},
journal = {Nucleic Acids Research},
volume = {48},
number = {19},
pages = {10890--10908},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
20.
Matthias Thoms, Robert Buschauer, Michael Ameismeier, Lennart Koepke, Timo Denk, Maximilian Hirschenberger, Hanna Kratzat, Manuel Hayn, Timur Mackens-Kiani, Jingdong Cheng, Jan H. Straub, Christina M. Stürzel, Thomas Fröhlich, Otto Berninghausen, Thomas Becker, Frank Kirchhoff, Konstantin M. J. Sparrer, Roland Beckmann
Structural basis for translational shutdown and immune evasion by the Nsp1 protein of SARS-CoV‑2 Journal Article
In: Science, vol. 369, no. 6508, pp. 1249 – 1255, 2020.
@article{Thoms2020,
title = {Structural basis for translational shutdown and immune evasion by the Nsp1 protein of SARS-CoV-2},
author = {Matthias Thoms and Robert Buschauer and Michael Ameismeier and Lennart Koepke and Timo Denk and Maximilian Hirschenberger and Hanna Kratzat and Manuel Hayn and Timur Mackens-Kiani and Jingdong Cheng and Jan H. Straub and Christina M. Stürzel and Thomas Fröhlich and Otto Berninghausen and Thomas Becker and Frank Kirchhoff and Konstantin M. J. Sparrer and Roland Beckmann},
doi = {10.1126/science.abc8665},
year = {2020},
date = {2020-09-01},
journal = {Science},
volume = {369},
number = {6508},
pages = {1249--1255},
keywords = {},
pubstate = {published},
tppubtype = {article}
}