HIV-1 Vpr antagonizes innate immune activation by targeting karyopherin-mediated NF- κB/IRF3 nuclear transport
- University College London, United Kingdom
Abstract
HIV-1 must replicate in cells that are equipped to defend themselves from infection through intracellular innate immune systems. HIV-1 evades innate immune sensing through encapsidated DNA synthesis and encodes accessory genes that antagonize specific antiviral effectors. Here we show that both particle associated, and expressed HIV-1 Vpr, antagonize the stimulatory effect of a variety of pathogen associated molecular patterns by inhibiting IRF3 and NF-κB nuclear transport. Phosphorylation of IRF3 at S396, but not S386, was also inhibited. We propose that, rather than promoting HIV-1 nuclear import, Vpr interacts with karyopherins to disturb their import of IRF3 and NF-κB to promote replication in macrophages. Concordantly, we demonstrate Vpr dependent rescue of HIV-1 replication in human macrophages from inhibition by cGAMP, the product of activated cGAS. We propose a model that unifies Vpr manipulation of nuclear import and inhibition of innate immune activation to promote HIV-1 replication and transmission.
Data availability
All data generated or analysed during this study are included in the manuscript and supporting files.
Article and author information
Author details
Lorena Zuliani-Alvarez
Funding
Wellcome Trust (Senior Biomedical Research Fellowship)
- Greg J Towers
H2020 European Research Council (Advanced Grant HIVinnate)
- Greg J Towers
Medical Research Council (PhD studentship)
- Hataf Khan
Medical Research Council (Clinical training fellowship)
- Chris Van Tulleken
Wellcome Trust (Collaborative Award)
- Greg J Towers
National Institute of Health Research (University College London Hospitals Biomedical Research Centre)
- Greg J Towers
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Reviewing Editor
- John W Schoggins, University of Texas Southwestern Medical Center, United States
Ethics
Human subjects: This study was approved by the UCL/UCLH Committees on the Ethics of Human Research, Committee Alpha reference (06/Q0502/92). All participants provided written informed consent and consent for publication.
Version history
- Received: July 7, 2020
- Accepted: December 9, 2020
- Accepted Manuscript published: December 10, 2020 (version 1)
- Accepted Manuscript updated: December 12, 2020 (version 2)
- Version of Record published: December 24, 2020 (version 3)
Copyright
© 2020, Khan 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 Vpr antagonizes innate immune activation by targeting karyopherin-mediated NF- κB/IRF3 nuclear transport
eLife 9:e60821.
https://doi.org/10.7554/eLife.60821
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