HIV-1 Vpr antagonizes innate immune activation by targeting karyopherin-mediated NF- κB/IRF3 nuclear transport
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
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.
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.
Reviewing Editor
- John W Schoggins, University of Texas Southwestern Medical Center, United States
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, Towers 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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