HIV-1 Vpu is a potent transcriptional suppressor of NF-κB-elicited antiviral immune responses
- Sanford Burnham Prebys Medical Discovery Institute, United States
- École Polytechnique Fédérale de Lausanne, Switzerland
- Ulm University Medical Center, Germany
Abstract
Many viral pathogens target innate sensing cascades and/or cellular transcription factors to suppress antiviral immune responses. Here, we show that the accessory viral protein U (Vpu) of HIV-1 exerts broad immunosuppressive effects by inhibiting activation of the transcription factor NF-κB. Global transcriptional profiling of infected CD4+ T-cells revealed that vpu-deficient HIV-1 strains induce substantially stronger immune responses than the respective wild type viruses. Gene set enrichment analyses and cytokine arrays showed that Vpu suppresses the expression of NF-κB targets including interferons and restriction factors. Mutational analyses demonstrated that this immunosuppressive activity of Vpu is independent of its ability to counteract the restriction factor and innate sensor tetherin. However, Vpu-mediated inhibition of immune activation required an arginine residue in the cytoplasmic domain that is critical for blocking NF-κB signaling downstream of tetherin. In summary, our findings demonstrate that HIV-1 Vpu potently suppresses NF-κB-elicited antiviral immune responses at the transcriptional level.
Data availability
RNA sequencing data have been uploaded to the Gene Expression Omnibus (GEO) database (accession number #GSE117655).
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HIV-1 Vpu exerts broad immunosuppressive effects by inhibiting NF-κB-dependent gene expressionNCBI Gene Expression Omnibus, GSE117655.
Article and author information
Author details
Funding
Deutsche Forschungsgemeinschaft (SPP 1923)
- Frank Kirchhoff
- Daniel Sauter
European Research Council
- Frank Kirchhoff
International Graduate School in Molecular Medicine Ulm
- Simon Langer
- Kristina Hopfensperger
- Dominik Hotter
Deutsche Forschungsgemeinschaft (404687549)
- Simon Langer
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Reviewing Editor
- Viviana Simon, Icahn School of Medicine at Mount Sinai, United States
Ethics
Human subjects: The use of human PBMCs was approved by the Ethics Committee of the Ulm University Medical Center (application #50/16). All donors were anonymized and provided informed written consent.
Version history
- Received: September 11, 2018
- Accepted: January 26, 2019
- Accepted Manuscript published: February 5, 2019 (version 1)
- Version of Record published: February 12, 2019 (version 2)
Copyright
© 2019, Langer et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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HIV-1 Vpu is a potent transcriptional suppressor of NF-κB-elicited antiviral immune responses
eLife 8:e41930.
https://doi.org/10.7554/eLife.41930
Further reading
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- Immunology and Inflammation
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Background:
Prinflammatory extracellular chromatin from neutrophil extracellular traps (NETs) and other cellular sources is found in COVID-19 patients and may promote pathology. We determined whether pulmonary administration of the endonuclease dornase alfa reduced systemic inflammation by clearing extracellular chromatin.
Methods:
Eligible patients were randomized (3:1) to the best available care including dexamethasone (R-BAC) or to BAC with twice-daily nebulized dornase alfa (R-BAC + DA) for seven days or until discharge. A 2:1 ratio of matched contemporary controls (CC-BAC) provided additional comparators. The primary endpoint was the improvement in C-reactive protein (CRP) over time, analyzed using a repeated-measures mixed model, adjusted for baseline factors.
Results:
We recruited 39 evaluable participants: 30 randomized to dornase alfa (R-BAC +DA), 9 randomized to BAC (R-BAC), and included 60 CC-BAC participants. Dornase alfa was well tolerated and reduced CRP by 33% compared to the combined BAC groups (T-BAC). Least squares (LS) mean post-dexamethasone CRP fell from 101.9 mg/L to 23.23 mg/L in R-BAC +DA participants versus a 99.5 mg/L to 34.82 mg/L reduction in the T-BAC group at 7 days; p=0.01. The anti-inflammatory effect of dornase alfa was further confirmed with subgroup and sensitivity analyses on randomised participants only, mitigating potential biases associated with the use of CC-BAC participants. Dornase alfa increased live discharge rates by 63% (HR 1.63, 95% CI 1.01–2.61, p=0.03), increased lymphocyte counts (LS mean: 1.08 vs 0.87, p=0.02) and reduced circulating cf-DNA and the coagulopathy marker D-dimer (LS mean: 570.78 vs 1656.96 μg/mL, p=0.004).
Conclusions:
Dornase alfa reduces pathogenic inflammation in COVID-19 pneumonia, demonstrating the benefit of cost-effective therapies that target extracellular chromatin.
Funding:
LifeArc, Breathing Matters, The Francis Crick Institute (CRUK, Medical Research Council, Wellcome Trust).
Clinical trial number:
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