HIV-1 Vpu is a potent transcriptional suppressor of NF-κB-elicited antiviral immune responses.

Simon Langer,Nikaïa Smith,Lukas Klein,Lars Pache,Kristina Hopfensperger,Daniel Sauter,Jacques Fellay,Johannes A Van Der Merwe,Frank Kirchhoff,Sumit K Chanda,Kristina M Herbert,Dominik Hotter,Christian Hammer,Paul D De Jesus

doi:10.7554/elife.41930

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.

Highlights

Efficient replication of human immunodeficiency virus (HIV) depends on its ability to counteract or evade a variety of antiviral defense mechanisms
To determine the effects of viral protein U (Vpu)-mediated tetherin counteraction and downstream inhibition of NF-kB signaling on immune activation, we generated HIV-1 mutants selectively impaired in either of these inhibitory activities (Figure 1A)
Besides its ability to decrease CD4 protein levels at the cell surface and to counteract tetherin, accumulating evidence suggested that HIV-1 Vpu exerts much broader immunosuppressive effects by inhibiting the activation of cellular transcription factors (Sauter and Kirchhoff, 2018)

Summary

Introduction

Efficient replication of human immunodeficiency virus (HIV) depends on its ability to counteract or evade a variety of antiviral defense mechanisms Both adaptive and innate immune responses exert tremendous selection pressure on the virus and form an environment that is hostile to viral replication. The success of HIV-1 in part depends on four so-called accessory proteins (Vif, Nef, Vpr, and Vpu) These viral proteins can be dispensable for viral replication in vitro, but are essential for high viral loads and efficient spread in vivo since they antagonize a variety of innate immune sensors and/or effectors. Vif, Vpr, and Vpu have all been suggested to inhibit expression of interferon-b (IFN-b) and potentially other antiviral genes by depleting the cellular transcription factor. Our results provide new insights into the transcriptional regulation of antiviral immune responses by HIV-1 and demonstrate that the viral protein U exerts broader immunosuppressive effects than previously known

Results

Discussion

Materials and methods