Publications

1.

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.

2.

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.

Abstract | Links

@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}

}

Close

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.

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3.

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.

Abstract | Links

@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}

}

Close

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.

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4.

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.