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

Maria C. Virgilio, Barkha Ramnani, Thomas Chen, W. Miguel Disbennett, Jay Lubow, Joshua D. Welch and Kathleen L. Collins ()
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Maria C. Virgilio: University of Michigan
Barkha Ramnani: University of Michigan
Thomas Chen: University of Michigan
W. Miguel Disbennett: University of Michigan
Jay Lubow: University of Michigan
Joshua D. Welch: University of Michigan
Kathleen L. Collins: University of Michigan

Nature Communications, 2024, vol. 15, issue 1, 1-19

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-49635-w

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