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HIV-1 Vpr combats the PU.1-driven antiviral response in primary human macrophages

Author

Listed:
  • Maria C. Virgilio

    (University of Michigan
    University of Michigan
    University of Michigan)

  • Barkha Ramnani

    (University of Michigan)

  • Thomas Chen

    (University of Michigan
    University of Michigan
    University of Michigan)

  • W. Miguel Disbennett

    (University of Michigan
    University of Michigan
    University of Pennsylvania)

  • Jay Lubow

    (University of Michigan
    Inc.)

  • Joshua D. Welch

    (University of Michigan
    University of Michigan)

  • Kathleen L. Collins

    (University of Michigan
    University of Michigan
    University of Michigan)

Abstract

HIV-1 Vpr promotes efficient spread of HIV-1 from macrophages to T cells by transcriptionally downmodulating restriction factors that target HIV-1 Envelope protein (Env). Here we find that Vpr induces broad transcriptomic changes by targeting PU.1, a transcription factor necessary for expression of host innate immune response genes, including those that target Env. Consistent with this, we find silencing PU.1 in infected macrophages lacking Vpr rescues Env. Vpr downmodulates PU.1 through a proteasomal degradation pathway that depends on physical interactions with PU.1 and DCAF1, a component of the Cul4A E3 ubiquitin ligase. The capacity for Vpr to target PU.1 is highly conserved across primate lentiviruses. In addition to impacting infected cells, we find that Vpr suppresses expression of innate immune response genes in uninfected bystander cells, and that virion-associated Vpr can degrade PU.1. Together, we demonstrate Vpr counteracts PU.1 in macrophages to blunt antiviral immune responses and promote viral spread.

Suggested Citation

  • Maria C. Virgilio & Barkha Ramnani & Thomas Chen & W. Miguel Disbennett & Jay Lubow & Joshua D. Welch & Kathleen L. Collins, 2024. "HIV-1 Vpr combats the PU.1-driven antiviral response in primary human macrophages," Nature Communications, Nature, vol. 15(1), pages 1-19, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-49635-w
    DOI: 10.1038/s41467-024-49635-w
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    References listed on IDEAS

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    2. Ruslan Medzhitov & Paula Preston-Hurlburt & Charles A. Janeway, 1997. "A human homologue of the Drosophila Toll protein signals activation of adaptive immunity," Nature, Nature, vol. 388(6640), pages 394-397, July.
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